Skip to main content
SpringerLink
Log in

The human HSP70 family of chaperones: where do we stand?

  • Mini Review
  • Published:
Cell Stress and Chaperones Aims and scope

Abstract

The 70-kDa heat shock protein (HSP70) family of molecular chaperones represents one of the most ubiquitous classes of chaperones and is highly conserved in all organisms. Members of the HSP70 family control all aspects of cellular proteostasis such as nascent protein chain folding, protein import into organelles, recovering of proteins from aggregation, and assembly of multi-protein complexes. These chaperones augment organismal survival and longevity in the face of proteotoxic stress by enhancing cell viability and facilitating protein damage repair. Extracellular HSP70s have a number of cytoprotective and immunomodulatory functions, the latter either in the context of facilitating the cross-presentation of immunogenic peptides via major histocompatibility complex (MHC) antigens or in the context of acting as “chaperokines” or stimulators of innate immune responses. Studies have linked the expression of HSP70s to several types of carcinoma, with Hsp70 expression being associated with therapeutic resistance, metastasis, and poor clinical outcome. In malignantly transformed cells, HSP70s protect cells from the proteotoxic stress associated with abnormally rapid proliferation, suppress cellular senescence, and confer resistance to stress-induced apoptosis including protection against cytostatic drugs and radiation therapy. All of the cellular activities of HSP70s depend on their adenosine-5′-triphosphate (ATP)-regulated ability to interact with exposed hydrophobic surfaces of proteins. ATP hydrolysis and adenosine diphosphate (ADP)/ATP exchange are key events for substrate binding and Hsp70 release during folding of nascent polypeptides. Several proteins that bind to distinct subdomains of Hsp70 and consequently modulate the activity of the chaperone have been identified as HSP70 co-chaperones. This review focuses on the regulation, function, and relevance of the molecular Hsp70 chaperone machinery to disease and its potential as a therapeutic target.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

17-AAG:

17-Allylamino-17-demethoxy-geldanamycin

ADD70:

AIF-derived decoy for HSP70

AIF:

Apoptosis-inducing factor

APC:

Antigen-presenting cell

BAG:

Bcl-2-associated athanogene

CHIP:

C-terminal Hsp70-interacting protein

CRLM:

Colorectal liver metastasis

CSC:

Cancer stem cell

DC:

Dendritic cell

DSG:

15-Deoxyspergualin

EGCG:

(−)-Epigallocatechin-3-gallate

ERK:

Extracellular signal-regulated kinase

FOLFOX:

5-Fluorouracil, leucovorin, and oxaliplatin

GGA:

Geranylgeranyl acetone

HCC:

Hepatocellular carcinoma

HIF:

Hypoxia-inducible factor

Hip:

Hsp70 interacting protein

Hop:

Hsp70/Hsp90 organizing protein

HSE:

Heat shock element

HSF:

Heat shock factor

HSP/Hsp:

Heat shock protein

HSR:

Heat shock response

JDP:

J-domain protein

JNK:

c-Jun N-terminal kinase

MB:

Methylene blue

mHsp:

Membrane-bound Hsp

MAPK:

Mitogen-activated protein kinase

MDSC:

Myeloid-derived suppressor cell

MMP:

Matrix metalloproteinase

mTOR:

Mammalian target of rapamycin

NBD:

Nucleotide binding domain

NEF:

Nucleotide exchange factor

NF-κB:

Nuclear factor kappa B

PES:

2-Phenylethynesulfonamide

NK:

Natural killer

NSCLC:

Nonsmall cell lung carcinoma

PI3K:

Phosphatidylinositol-3 kinase

SBD:

Substrate binding domain

SGC:

Sulfogalactosylceramide

SIGLEC/Siglec:

Sialic acid-binding immunoglobulin-like lectin

STAT:

Signal transducer and activator of transcription

TGF:

Transforming growth factor

TNF:

Tumor necrosis factor

References

  • Abe M, Manola JB, Oh WK et al (2004) Plasma levels of heat shock protein 70 in patients with prostate cancer: a potential biomarker for prostate cancer. Clin Prostate Cancer 3:49–53

    Article  CAS  PubMed  Google Scholar 

  • Abisambra J, Jinwal UK, Miyata Y et al (2013) Allosteric heat shock protein 70 inhibitors rapidly rescue synaptic plasticity deficits by reducing aberrant tau. Biol Psychiatry 74:367–374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aggarwal BB, Gehlot P (2009) Inflammation and cancer: how friendly is the relationship for cancer patients? Curr Opin Pharmacol 9:351–369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ahmad A, Bhattacharya A, McDonald RA et al (2011) Heat shock protein 70 kDa chaperone/DnaJ cochaperone complex employs an unusual dynamic interface. Proc Natl Acad Sci U S A 108:18966–18971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Akerfelt M, Morimoto RI, Sistonen L (2010) Heat shock factors: integrators of cell stress, development and lifespan. Nat Rev Mol Cell Biol 11:545–555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Akira S, Isshiki H, Nakajima T et al (1992) Regulation of expression of the interleukin 6 gene: structure and function of the transcription factor NF-IL6. Ciba Found Symp 167:47–62

    CAS  PubMed  Google Scholar 

  • Alexiou GA, Vartholomatos G, Stefanaki K et al (2013) Expression of heat shock proteins in medulloblastoma. J Neurosurg Pediatr 12:452–457

    Article  PubMed  Google Scholar 

  • Alexiou GA, Karamoutsios A, Lallas G et al (2014) Expression of heat shock proteins in brain tumors. Turk Neurosurg 24:745–749

    PubMed  Google Scholar 

  • Angelo LS, Wu JY, Meng F et al (2011) Combining curcumin (diferuloylmethane) and heat shock protein inhibition for neurofibromatosis 2 treatment: analysis of response and resistance pathways. Mol Cancer Ther 10:2094–2103

    Article  CAS  PubMed  Google Scholar 

  • Angelo LS, Maxwell DS, Wu JY et al (2013) Binding partners for curcumin in human schwannoma cells: biologic implications. Bioorg Med Chem 21:932–939

    Article  CAS  PubMed  Google Scholar 

  • Arakawa A, Handa N, Shirouzu M, Yokoyama S (2011) Biochemical and structural studies on the high affinity of Hsp70 for ADP. Protein Sci 20:1367–1379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arispe N, De Maio A (2000) ATP and ADP modulate a cation channel formed by Hsc70 in acidic phospholipid membranes. J Biol Chem 275:30839–30843

    Article  CAS  PubMed  Google Scholar 

  • Arnold-Schild D, Hanau D, Spehner D et al (1999) Cutting edge: receptor-mediated endocytosis of heat shock proteins by professional antigen-presenting cells. J Immunol 162:3757–3760

    CAS  PubMed  Google Scholar 

  • Asea A, Kraeft SK, Kurt-Jones EA et al (2000) HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 6:435–442

    Article  CAS  PubMed  Google Scholar 

  • Asea A, Rehli M, Kabingu E et al (2002) Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 277:15028–15034

    Article  CAS  PubMed  Google Scholar 

  • Athanassiadou P, Petrakakou E, Sakelariou V et al (1998) Expression of p53, bcl-2 and heat shock protein (hsp72) in malignant and benign ovarian tumours. Eur J Cancer Prev 7:225–231

    Article  CAS  PubMed  Google Scholar 

  • Balaburski GM, Leu JI, Beeharry N et al (2013) A modified HSP70 inhibitor shows broad activity as an anticancer agent. Mol Cancer Res 11:219–229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Balakrishnan K, Murali V, Rathika C et al (2014) Hsp70 is an independent stress marker among frequent users of mobile phones. J Environ Pathol Toxicol Oncol 33:339–347

    Article  PubMed  Google Scholar 

  • Ballinger CA, Connell P, Wu Y et al (1999) Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions. Mol Cell Biol 19:4535–4545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK (2000) Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int Immunol 12:1539–1546

    Article  CAS  PubMed  Google Scholar 

  • Bausero MA, Page DT, Osinaga E, Asea A (2004) Surface expression of Hsp25 and Hsp72 differentially regulates tumor growth and metastasis. Tumour Biol 25:243–251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bausero MA, Gastpar R, Multhoff G, Asea A (2005) Alternative mechanism by which IFN-gamma enhances tumor recognition: active release of heat shock protein 72. J Immunol 175:2900–2912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bayer C, Liebhardt ME, Schmid TE et al (2014) Validation of heat shock protein 70 as a tumor-specific biomarker for monitoring the outcome of radiation therapy in tumor mouse models. Int J Radiat Oncol Biol Phys 88:694–700

    Article  CAS  PubMed  Google Scholar 

  • Beere HM, Wolf BB, Cain K et al (2000) Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol 2:469–475

    Article  CAS  PubMed  Google Scholar 

  • Bertelsen EB, Chang L, Gestwicki JE, Zuiderweg ER (2009) Solution conformation of wild-type E. coli Hsp70 (DnaK) chaperone complexed with ADP and substrate. Proc Natl Acad Sci U S A 106:8471–8476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Binder RJ, Vatner R, Srivastava P (2004) The heat-shock protein receptors: some answers and more questions. Tissue Antigens 64:442–451

    Article  CAS  PubMed  Google Scholar 

  • Boiocchi C, Osera C, Monti MC et al (2014) Are Hsp70 protein expression and genetic polymorphism implicated in multiple sclerosis inflammation? J Neuroimmunol 268:84–88

    Article  CAS  PubMed  Google Scholar 

  • Borges TJ, Wieten L, van Herwijnen MJ et al (2012) The anti-inflammatory mechanisms of Hsp70. Front Immunol 3:95

    Article  PubMed  PubMed Central  Google Scholar 

  • Boulanger J, Faulds D, Eddy EM, Lingwood CA (1995) Members of the 70 kDa heat shock protein family specifically recognize sulfoglycolipids: role in gamete recognition and mycoplasma-related infertility. J Cell Physiol 165:7–17

    Article  CAS  PubMed  Google Scholar 

  • Braunstein MJ, Scott SS, Scott CM et al (2011) Antimyeloma effects of the heat shock protein 70 molecular chaperone inhibitor MAL3-101. J Oncol 2011:232037

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Breuninger S, Erl J, Knape C et al (2014) Quantitative analysis of liposomal heat shock protein 70 (Hsp70) in the blood of tumor patients using a novel lipHsp70 ELISA. J Clin Cell Immunol 5:5

    Article  Google Scholar 

  • Brocchieri L, de Conway ME, Macario AJ (2008) hsp70 genes in the human genome: conservation and differentiation patterns predict a wide array of overlapping and specialized functions. BMC Evol Biol 8:19

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Brodsky JL (1999) Selectivity of the molecular chaperone-specific immunosuppressive agent 15-deoxyspergualin: modulation of Hsc70 ATPase activity without compromising DnaJ chaperone interactions. Biochem Pharmacol 57:877–880

    Article  CAS  PubMed  Google Scholar 

  • Broquet AH, Thomas G, Masliah J, Trugnan G, Bachelet M (2003) Expression of the molecular chaperone Hsp70 in detergent-resistant microdomains correlates with its membrane delivery and release. J Biol Chem 278:21601–21606

    Article  CAS  PubMed  Google Scholar 

  • Calderwood SK, Gong J (2012) Molecular chaperones in mammary cancer growth and breast tumor therapy. J Cell Biochem 113:1096–1103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chalmin F, Ladoire S, Mignot G et al (2010) Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Invest 120:457–471

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chang L, Miyata Y, Ung PM et al (2011) Chemical screens against a reconstituted multiprotein complex: myricetin blocks DnaJ regulation of DnaK through an allosteric mechanism. Chem Biol 18:210–221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen J, Ren J, Gu G et al (2013) Crohn’s disease and polymorphism of heat shock protein gene HSP70-2 in the Chinese population. J Gastroenterol Hepatol 28:814–818

    Article  CAS  PubMed  Google Scholar 

  • Chen GY, Brown NK, Wu W et al (2014) Broad and direct interaction between TLR and Siglec families of pattern recognition receptors and its regulation by Neu1. Elife 3:e04066

    PubMed  PubMed Central  Google Scholar 

  • Chendil D, Ranga RS, Meigooni D, Sathishkumar S, Ahmed MM (2004) Curcumin confers radiosensitizing effect in prostate cancer cell line PC-3. Oncogene 23:1599–1607

    Article  CAS  PubMed  Google Scholar 

  • Chi W, Meng F, Li Y et al (2014) Downregulation of miRNA-134 protects neural cells against ischemic injury in N2A cells and mouse brain with ischemic stroke by targeting HSPA12B. Neuroscience 277:111–122

    Article  CAS  PubMed  Google Scholar 

  • Chiba Y, Kubota T, Watanabe M et al (1998) MKT-077, localized lipophilic cation: antitumor activity against human tumor xenografts serially transplanted into nude mice. Anticancer Res 18:1047–1052

    CAS  PubMed  Google Scholar 

  • Cho HJ, Gee HY, Baek KH et al (2011) A small molecule that binds to an ATPase domain of Hsc70 promotes membrane trafficking of mutant cystic fibrosis transmembrane conductance regulator. J Am Chem Soc 133:20267–20276

    Article  CAS  PubMed  Google Scholar 

  • Chou SD, Prince T, Gong J, Calderwood SK (2012) mTOR is essential for the proteotoxic stress response, HSF1 activation and heat shock protein synthesis. PLoS ONE 7:e39679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chuma M, Sakamoto M, Yamazaki K et al (2003) Expression profiling in multistage hepatocarcinogenesis: identification of HSP70 as a molecular marker of early hepatocellular carcinoma. Hepatology 37:198–207

    Article  CAS  PubMed  Google Scholar 

  • Ciocca DR, Calderwood SK (2005) Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 10:86–103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ciocca DR, Frayssinet P, Cuello-Carrion FD (2007) A pilot study with a therapeutic vaccine based on hydroxyapatite ceramic particles and self-antigens in cancer patients. Cell Stress Chaperones 12:33–43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ciocca DR, Cayado-Gutierrez N, Maccioni M, Cuello-Carrion FD (2012) Heat shock proteins (HSPs) based anti-cancer vaccines. Curr Mol Med 12:1183–1197

    Article  CAS  PubMed  Google Scholar 

  • Ciocca DR, Arrigo AP, Calderwood SK (2013) Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update. Arch Toxicol 87:19–48

    Article  CAS  PubMed  Google Scholar 

  • Collison LW, Workman CJ, Kuo TT et al (2007) The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450:566–569

    Article  CAS  PubMed  Google Scholar 

  • Colvin TA, Gabai VL, Gong J et al (2014) Hsp70-Bag3 interactions regulate cancer-related signaling networks. Cancer Res 74:4731–4740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Congdon EE, Wu JW, Myeku N et al (2012) Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo. Autophagy 8:609–622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Connell P, Ballinger CA, Jiang J et al (2001) The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nat Cell Biol 3:93–96

    Article  CAS  PubMed  Google Scholar 

  • Craig EA (1985) The stress response: changes in eukaryotic gene expression in response to environmental stress. Science 230:800–801

    Article  CAS  PubMed  Google Scholar 

  • Craig EA, Huang P, Aron R, Andrew A (2006) The diverse roles of J-proteins, the obligate Hsp70 co-chaperone. Rev Physiol Biochem Pharmacol 156:1–21

    CAS  PubMed  Google Scholar 

  • Daugaard M, Jäättelä M, Rohde M (2005) Hsp70-2 is required for tumor cell growth and survival. Cell Cycle 4:877–880

    Article  CAS  PubMed  Google Scholar 

  • Daugaard M, Kirkegaard-Sorensen T, Ostenfeld MS et al (2007a) Lens epithelium-derived growth factor is an Hsp70-2 regulated guardian of lysosomal stability in human cancer. Cancer Res 67:2559–2567

    Article  CAS  PubMed  Google Scholar 

  • Daugaard M, Rohde M, Jäättelä M (2007b) The heat shock protein 70 family: highly homologous proteins with overlapping and distinct functions. FEBS Lett 581:3702–3710

    Article  CAS  PubMed  Google Scholar 

  • Dhingra K, Valero V, Gutierrez L et al (1994) Phase II study of deoxyspergualin in metastatic breast cancer. Invest New Drugs 12:235–241

    Article  CAS  PubMed  Google Scholar 

  • Dong J, Guo L, Liao Z et al (2013) Increased expression of heat shock protein 70 in chronic obstructive pulmonary disease. Int Immunopharmacol 17:885–893

    Article  CAS  PubMed  Google Scholar 

  • Dulin E, Garcia-Barreno P, Guisasola MC (2010) Extracellular heat shock protein 70 (HSPA1A) and classical vascular risk factors in a general population. Cell Stress Chaperones 15:929–937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dutta SK, Girotra M, Singla M et al (2012) Serum HSP70: a novel biomarker for early detection of pancreatic cancer. Pancreas 41:530–534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duval A, Olaru D, Campos L et al (2006) Expression and prognostic significance of heat-shock proteins in myelodysplastic syndromes. Haematologica 91:713–714

    CAS  PubMed  Google Scholar 

  • Dworniczak B, Mirault ME (1987) Structure and expression of a human gene coding for a 71 kd heat shock ‘cognate’ protein. Nucleic Acids Res 15:5181–5197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Enomoto Y, Bharti A, Khaleque AA et al (2006) Enhanced immunogenicity of heat shock protein 70 peptide complexes from dendritic cell-tumor fusion cells. J Immunol 177:5946–5955

    Article  CAS  PubMed  Google Scholar 

  • Erickson RR, Dunning LM, Holtzman JL (2006) The effect of aging on the chaperone concentrations in the hepatic, endoplasmic reticulum of male rats: the possible role of protein misfolding due to the loss of chaperones in the decline in physiological function seen with age. J Gerontol A Biol Sci Med Sci 61:435–443

    Article  PubMed  Google Scholar 

  • Ermakova SP, Kang BS, Choi BY et al (2006) (−)-Epigallocatechin gallate overcomes resistance to etoposide-induced cell death by targeting the molecular chaperone glucose-regulated protein 78. Cancer Res 66:9260–9269

    Article  CAS  PubMed  Google Scholar 

  • Evans CG, Chang L, Gestwicki JE (2010) Heat shock protein 70 (hsp70) as an emerging drug target. J Med Chem 53:4585–4602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Evans LE, Cheeseman MD, Yahya N, Jones K (2015) Investigating apoptozole as a chemical probe for HSP70 inhibition. PLoS ONE 10:e0140006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Evdonin AL, Guzhova IV, Margulis BA, Medvedeva ND (2004) Phospholipase c inhibitor, u73122, stimulates release of hsp-70 stress protein from A431 human carcinoma cells. Cancer Cell Int 4:2

    Article  PubMed  PubMed Central  Google Scholar 

  • Evdonin AL, Martynova MG, Bystrova OA et al (2006) The release of Hsp70 from A431 carcinoma cells is mediated by secretory-like granules. Eur J Cell Biol 85:443–455

    Article  CAS  PubMed  Google Scholar 

  • Fesler A, Xu X, Zheng X et al (2015) Identification of miR-215 mediated targets/pathways via translational immunoprecipitation expression analysis (TrIP-chip). Oncotarget 6:24463–24473

    Article  PubMed  PubMed Central  Google Scholar 

  • Fewell SW, Day BW, Brodsky JL (2001) Identification of an inhibitor of hsc70-mediated protein translocation and ATP hydrolysis. J Biol Chem 276:910–914

    Article  CAS  PubMed  Google Scholar 

  • Finka A, Sharma SK, Goloubinoff P (2015a) Multi-layered molecular mechanisms of polypeptide holding, unfolding and disaggregation by HSP70/HSP110 chaperones. Front Mol Biosci 2:29

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Finka A, Sood V, Quadroni M, Rios PL, Goloubinoff P (2015b) Quantitative proteomics of heat-treated human cells show an across-the-board mild depletion of housekeeping proteins to massively accumulate few HSPs. Cell Stress Chaperones 20:605–620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Flaherty KM, Luca-Flaherty C, McKay DB (1990) Three-dimensional structure of the ATPase fragment of a 70K heat-shock cognate protein. Nature 346:623–628

    Article  CAS  PubMed  Google Scholar 

  • Fong JJ, Sreedhara K, Deng L et al (2015) Immunomodulatory activity of extracellular Hsp70 mediated via paired receptors Siglec-5 and Siglec-14. EMBO J 34:2775–2788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • French JB, Zhao H, An S et al (2013) Hsp70/Hsp90 chaperone machinery is involved in the assembly of the purinosome. Proc Natl Acad Sci U S A 110:2528–2533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frisan E, Vandekerckhove J, De TA et al (2012) Defective nuclear localization of Hsp70 is associated with dyserythropoiesis and GATA-1 cleavage in myelodysplastic syndromes. Blood 119:1532–1542

    Article  CAS  PubMed  Google Scholar 

  • Gabai VL, Meriin AB, Mosser DD et al (1997) Hsp70 prevents activation of stress kinases. A novel pathway of cellular thermotolerance. J Biol Chem 272:18033–18037

    Article  CAS  PubMed  Google Scholar 

  • Gabai VL, Budagova KR, Sherman MY (2005) Increased expression of the major heat shock protein Hsp72 in human prostate carcinoma cells is dispensable for their viability but confers resistance to a variety of anticancer agents. Oncogene 24:3328–3338

    Article  CAS  PubMed  Google Scholar 

  • Galazka G, Jurewicz A, Domowicz M et al (2014) HINT1 peptide/Hsp70 complex induces NK-cell-dependent immunoregulation in a model of autoimmune demyelination. Eur J Immunol 44:3026–3044

    Article  CAS  PubMed  Google Scholar 

  • Gao Y, Han C, Huang H et al (2010) Heat shock protein 70 together with its co-chaperone CHIP inhibits TNF-alpha induced apoptosis by promoting proteasomal degradation of apoptosis signal-regulating kinase1. Apoptosis 15:822–833

    Article  CAS  PubMed  Google Scholar 

  • Garamvolgyi Z, Prohaszka Z, Rigo J Jr, Kecskemeti A, Molvarec A (2015) Increased circulating heat shock protein 70 (HSPA1A) levels in gestational diabetes mellitus: a pilot study. Cell Stress Chaperones 20:575–581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garg AK, Buchholz TA, Aggarwal BB (2005) Chemosensitization and radiosensitization of tumors by plant polyphenols. Antioxid Redox Signal 7:1630–1647

    Article  CAS  PubMed  Google Scholar 

  • Gastpar R, Gehrmann M, Bausero MA et al (2005) Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res 65:5238–5247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gehrmann M, Pfister K, Hutzler P et al (2002) Effects of antineoplastic agents on cytoplasmic and membrane-bound heat shock protein 70 (Hsp70) levels. Biol Chem 383:1715–1725

    CAS  PubMed  Google Scholar 

  • Gehrmann M, Marienhagen J, Eichholtz-Wirth H et al (2005) Dual function of membrane-bound heat shock protein 70 (Hsp70), Bag-4, and Hsp40: protection against radiation-induced effects and target structure for natural killer cells. Cell Death Differ 12:38–51

    Article  CAS  PubMed  Google Scholar 

  • Gehrmann M, Liebisch G, Schmitz G et al (2008a) Tumor-specific Hsp70 plasma membrane localization is enabled by the glycosphingolipid Gb3. PLoS ONE 3:e1925

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gehrmann M, Radons J, Molls M, Multhoff G (2008b) The therapeutic implications of clinically applied modifiers of heat shock protein 70 (Hsp70) expression by tumor cells. Cell Stress Chaperones 13:1–10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gehrmann M, Stangl S, Kirschner A et al (2012) Immunotherapeutic targeting of membrane Hsp70-expressing tumors using recombinant human granzyme B. PLoS ONE 7:e41341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gehrmann M, Cervello M, Montalto G et al (2014a) Heat shock protein 70 serum levels differ significantly in patients with chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Front Immunol 5:307

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gehrmann M, Specht HM, Bayer C et al (2014b) Hsp70—a biomarker for tumor detection and monitoring of outcome of radiation therapy in patients with squamous cell carcinoma of the head and neck. Radiat Oncol 9:131

    Article  PubMed  PubMed Central  Google Scholar 

  • Gehrmann MK, Kimm MA, Stangl S et al (2015) Imaging of Hsp70-positive tumors with cmHsp70.1 antibody-conjugated gold nanoparticles. Int J Nanomedicine 10:5687–5700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giannakopoulos NV, Luo JK, Papov V et al (2005) Proteomic identification of proteins conjugated to ISG15 in mouse and human cells. Biochem Biophys Res Commun 336:496–506

    Article  CAS  PubMed  Google Scholar 

  • Goloudina AR, Demidov ON, Garrido C (2012) Inhibition of HSP70: a challenging anti-cancer strategy. Cancer Lett 325:117–124

    Article  CAS  PubMed  Google Scholar 

  • Gong J, Zhang Y, Durfee J et al (2010) A heat shock protein 70-based vaccine with enhanced immunogenicity for clinical use. J Immunol 184:488–496

    Article  CAS  PubMed  Google Scholar 

  • Grave E, Yokota S, Yamamoto S et al (2015) Geranylgeranylacetone selectively binds to the HSP70 of Helicobacter pylori and alters its coccoid morphology. Sci Rep 5:13738

    Article  PubMed  PubMed Central  Google Scholar 

  • Greene MK, Maskos K, Landry SJ (1998) Role of the J-domain in the cooperation of Hsp40 with Hsp70. Proc Natl Acad Sci U S A 95:6108–6113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gross C, Koelch W, DeMaio A, Arispe N, Multhoff G (2003) Cell surface-bound heat shock protein 70 (Hsp70) mediates perforin-independent apoptosis by specific binding and uptake of granzyme B. J Biol Chem 278:41173–41181

    Article  CAS  PubMed  Google Scholar 

  • Gunther S, Ostheimer C, Stangl S et al (2015) Correlation of Hsp70 serum levels with gross tumor volume and composition of lymphocyte subpopulations in patients with squamous cell and adeno non-small cell lung cancer. Front Immunol 6:556

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Guo F, Rocha K, Bali P et al (2005a) Abrogation of heat shock protein 70 induction as a strategy to increase antileukemia activity of heat shock protein 90 inhibitor 17-allylamino-demethoxy geldanamycin. Cancer Res 65:10536–10544

    Article  CAS  PubMed  Google Scholar 

  • Guo F, Sigua C, Bali P et al (2005b) Mechanistic role of heat shock protein 70 in Bcr-Abl-mediated resistance to apoptosis in human acute leukemia cells. Blood 105:1246–1255

    Article  CAS  PubMed  Google Scholar 

  • Guo W, Yan L, Yang L et al (2014) Targeting GRP75 improves HSP90 inhibitor efficacy by enhancing p53-mediated apoptosis in hepatocellular carcinoma. PLoS ONE 9:e85766

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gurbuxani S, Schmitt E, Cande C et al (2003) Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor. Oncogene 22:6669–6678

    Article  CAS  PubMed  Google Scholar 

  • Guzhova IV, Darieva ZA, Melo AR, Margulis BA (1997) Major stress protein Hsp70 interacts with NF-kB regulatory complex in human T-lymphoma cells. Cell Stress Chaperones 2:132–139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han Z, Truong QA, Park S, Breslow JL (2003) Two Hsp70 family members expressed in atherosclerotic lesions. Proc Natl Acad Sci U S A 100:1256–1261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hantschel M, Pfister K, Jordan A et al (2000) Hsp70 plasma membrane expression on primary tumor biopsy material and bone marrow of leukemic patients. Cell Stress Chaperones 5:438–442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Härdtner C, Multhoff G, Falk W, Radons J (2012) (−)-Epigallocatechin-3-gallate, a green tea-derived catechin, synergizes with celecoxib to inhibit IL-1-induced tumorigenic mediators by human pancreatic adenocarcinoma cells Colo357. Eur J Pharmacol 684:36–43

    Article  PubMed  CAS  Google Scholar 

  • Harrison GS, Drabkin HA, Kao FT et al (1987) Chromosomal location of human genes encoding major heat-shock protein HSP70. Somat Cell Mol Genet 13:119–130

    Article  CAS  PubMed  Google Scholar 

  • Harrison CJ, Hayer-Hartl M, Di LM, Hartl F, Kuriyan J (1997) Crystal structure of the nucleotide exchange factor GrpE bound to the ATPase domain of the molecular chaperone DnaK. Science 276:431–435

    Article  CAS  PubMed  Google Scholar 

  • Hartl FU (1996) Molecular chaperones in cellular protein folding. Nature 381:571–579

    Article  CAS  PubMed  Google Scholar 

  • Hayashida N, Fujimoto M, Tan K et al (2010) Heat shock factor 1 ameliorates proteotoxicity in cooperation with the transcription factor NFAT. EMBO J 29:3459–3469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He L, Deng T, Luo HS (2014) Heat shock protein 70 gene polymorphisms and cancer risk: a meta-analysis. ScientificWorldJournal 2014:540309

    PubMed  PubMed Central  Google Scholar 

  • Heath WR, Carbone FR (2009) Dendritic cell subsets in primary and secondary T cell responses at body surfaces. Nat Immunol 10:1237–1244

    Article  CAS  PubMed  Google Scholar 

  • Heck TG, Scholer CM, de Bittencourt PI (2011) HSP70 expression: does it a novel fatigue signalling factor from immune system to the brain? Cell Biochem Funct 29:215–226

    Article  CAS  PubMed  Google Scholar 

  • Henderson B, Pockley AG (2010) Molecular chaperones and protein-folding catalysts as intercellular signaling regulators in immunity and inflammation. J Leukoc Biol 88:445–462

    Article  CAS  PubMed  Google Scholar 

  • Henderson B, Calderwood SK, Coates AR et al (2010) Caught with their PAMPs down? The extracellular signalling actions of molecular chaperones are not due to microbial contaminants. Cell Stress Chaperones 15:123–141

    Article  CAS  PubMed  Google Scholar 

  • Hernandez MP, Sullivan WP, Toft DO (2002) The assembly and intermolecular properties of the hsp70-Hop-hsp90 molecular chaperone complex. J Biol Chem 277:38294–38304

    Article  CAS  PubMed  Google Scholar 

  • Hightower LE, Guidon PT Jr (1989) Selective release from cultured mammalian cells of heat-shock (stress) proteins that resemble glia-axon transfer proteins. J Cell Physiol 138:257–266

    Article  CAS  PubMed  Google Scholar 

  • Hirakawa T, Rokutan K, Nikawa T, Kishi K (1996) Geranylgeranylacetone induces heat shock proteins in cultured guinea pig gastric mucosal cells and rat gastric mucosa. Gastroenterology 111:345–357

    Article  CAS  PubMed  Google Scholar 

  • Hoffmann J, Junker H, Schmieder A et al (2011) EGCG downregulates IL-1RI expression and suppresses IL-1-induced tumorigenic factors in human pancreatic adenocarcinoma cells. Biochem Pharmacol 82:1153–1162

    Article  CAS  PubMed  Google Scholar 

  • Höhfeld J, Minami Y, Hartl FU (1995) Hip, a novel cochaperone involved in the eukaryotic Hsc70/Hsp40 reaction cycle. Cell 83:589–598

    Article  PubMed  Google Scholar 

  • Holtz WA, O’Malley KL (2003) Parkinsonian mimetics induce aspects of unfolded protein response in death of dopaminergic neurons. J Biol Chem 278:19367–19377

    Article  CAS  PubMed  Google Scholar 

  • Hom LL, Lee EC, Apicella JM et al (2012) Eleven days of moderate exercise and heat exposure induces acclimation without significant HSP70 and apoptosis responses of lymphocytes in college-aged males. Cell Stress Chaperones 17:29–39

    Article  CAS  PubMed  Google Scholar 

  • Hönicke AS, Ender SA, Radons J (2012) Combined administration of EGCG and IL-1 receptor antagonist efficiently downregulates IL-1-induced tumorigenic factors in U-2 OS human osteosarcoma cells. Int J Oncol 41:753–758

    PubMed  Google Scholar 

  • Hoozemans JJ, van Haastert ES, Nijholt DA, Rozemuller AJ, Scheper W (2012) Activation of the unfolded protein response is an early event in Alzheimer’s and Parkinson’s disease. Neurodegener Dis 10:212–215

    Article  CAS  PubMed  Google Scholar 

  • Horn P, Kalz A, Lim CL et al (2007) Exercise-recruited NK cells display exercise-associated eHSP-70. Exerc Immunol Rev 13:100–111

    PubMed  Google Scholar 

  • Horvath I, Multhoff G, Sonnleitner A, Vigh L (2008) Membrane-associated stress proteins: more than simply chaperones. Biochim Biophys Acta 1778:1653–1664

    Article  CAS  PubMed  Google Scholar 

  • Hu G, Tang J, Zhang B et al (2006) A novel endothelial-specific heat shock protein HspA12B is required in both zebrafish development and endothelial functions in vitro. J Cell Sci 119:4117–4126

    Article  CAS  PubMed  Google Scholar 

  • Hwang TS, Han HS, Choi HK et al (2003) Differential, stage-dependent expression of Hsp70, Hsp110 and Bcl-2 in colorectal cancer. J Gastroenterol Hepatol 18:690–700

    Article  PubMed  Google Scholar 

  • Jakobsson ME, Moen A, Bousset L et al (2013) Identification and characterization of a novel human methyltransferase modulating Hsp70 protein function through lysine methylation. J Biol Chem 288:27752–27763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • James MI, Iwuji C, Irving G et al (2015) Curcumin inhibits cancer stem cell phenotypes in ex vivo models of colorectal liver metastases, and is clinically safe and tolerable in combination with FOLFOX chemotherapy. Cancer Lett 364:135–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jang KW, Lee JE, Kim SY et al (2011) The C-terminus of Hsp70-interacting protein promotes Met receptor degradation. J Thorac Oncol 6:679–687

    Article  PubMed  Google Scholar 

  • Jenei ZM, Gombos T, Forhecz Z et al (2013) Elevated extracellular HSP70 (HSPA1A) level as an independent prognostic marker of mortality in patients with heart failure. Cell Stress Chaperones 18:809–813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ji Z, Lu R, Mou L et al (2014) Expressions of miR-15a and its target gene HSPA1B in the spermatozoa of patients with varicocele. Reproduction 147:693–701

    Article  CAS  PubMed  Google Scholar 

  • Jiang M, Abend JR, Johnson SF, Imperiale MJ (2009) The role of polyomaviruses in human disease. Virology 384:266–273

    Article  CAS  PubMed  Google Scholar 

  • Jinwal UK, Miyata Y, Koren J III et al (2009) Chemical manipulation of hsp70 ATPase activity regulates tau stability. J Neurosci 29:12079–12088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaiser M, Kuhnl A, Reins J et al (2011) Antileukemic activity of the HSP70 inhibitor pifithrin-mu in acute leukemia. Blood Cancer J 1, e28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kampinga HH, Craig EA (2010) The HSP70 chaperone machinery: J proteins as drivers of functional specificity. Nat Rev Mol Cell Biol 11:579–592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaur J, Srivastava A, Ralhan R (1998) Expression of 70-kDa heat shock protein in oral lesions: marker of biological stress or pathogenicity. Oral Oncol 34:496–501

    Article  CAS  PubMed  Google Scholar 

  • Kawanishi K, Shiozaki H, Doki Y et al (1999) Prognostic significance of heat shock proteins 27 and 70 in patients with squamous cell carcinoma of the esophagus. Cancer 85:1649–1657

    Article  CAS  PubMed  Google Scholar 

  • Khaleque MA, Bharti A, Sawyer D et al (2005) Induction of heat shock proteins by heregulin beta1 leads to protection from apoptosis and anchorage-independent growth. Oncogene 24:6564–6573

    CAS  PubMed  Google Scholar 

  • Kinoshita S, Akira S, Kishimoto T (1992) A member of the C/EBP family, NF-IL6 beta, forms a heterodimer and transcriptionally synergizes with NF-IL6. Proc Natl Acad Sci U S A 89:1473–1476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kityk R, Kopp J, Sinning I, Mayer MP (2012) Structure and dynamics of the ATP-bound open conformation of Hsp70 chaperones. Mol Cell 48:863–874

    Article  CAS  PubMed  Google Scholar 

  • Kleinjung T, Arndt O, Feldmann HJ et al (2003) Heat shock protein 70 (Hsp70) membrane expression on head-and-neck cancer biopsy-a target for natural killer (NK) cells. Int J Radiat Oncol Biol Phys 57:820–826

    Article  CAS  PubMed  Google Scholar 

  • Koren J, Jinwal UK, Jin Y et al (2010) Facilitating Akt clearance via manipulation of Hsp70 activity and levels. J Biol Chem 285:2498–2505

    Article  CAS  PubMed  Google Scholar 

  • Koren J, Miyata Y, Kiray J et al (2012) Rhodacyanine derivative selectively targets cancer cells and overcomes tamoxifen resistance. PLoS ONE 7:e35566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kotoglou P, Kalaitzakis A, Vezyraki P et al (2009) Hsp70 translocates to the nuclei and nucleoli, binds to XRCC1 and PARP-1, and protects HeLa cells from single-strand DNA breaks. Cell Stress Chaperones 14:391–406

    Article  CAS  PubMed  Google Scholar 

  • Koya K, Li Y, Wang H et al (1996) MKT-077, a novel rhodacyanine dye in clinical trials, exhibits anticarcinoma activity in preclinical studies based on selective mitochondrial accumulation. Cancer Res 56:538–543

    CAS  PubMed  Google Scholar 

  • Kragol G, Hoffmann R, Chattergoon MA et al (2002) Identification of crucial residues for the antibacterial activity of the proline-rich peptide, pyrrhocoricin. Eur J Biochem 269:4226–4237

    Article  CAS  PubMed  Google Scholar 

  • Krause SW, Gastpar R, Andreesen R et al (2004) Treatment of colon and lung cancer patients with ex vivo heat shock protein 70-peptide-activated, autologous natural killer cells: a clinical phase i trial. Clin Cancer Res 10:3699–3707

    Article  CAS  PubMed  Google Scholar 

  • Kroeger H, Messah C, Ahern K et al (2012) Induction of endoplasmic reticulum stress genes, BiP and chop, in genetic and environmental models of retinal degeneration. Invest Ophthalmol Vis Sci 53:7590–7599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kronenberg M (2005) Toward an understanding of NKT cell biology: progress and paradoxes. Annu Rev Immunol 23:877–900

    Article  CAS  PubMed  Google Scholar 

  • Lancaster GI, Febbraio MA (2005) Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins. J Biol Chem 280:23349–23355

    Article  CAS  PubMed  Google Scholar 

  • Lanneau D, Brunet M, Frisan E et al (2008) Heat shock proteins: essential proteins for apoptosis regulation. J Cell Mol Med 12:743–761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lazaris AC, Theodoropoulos GE, Aroni K, Saetta A, Davaris PS (1995) Immunohistochemical expression of C-myc oncogene, heat shock protein 70 and HLA-DR molecules in malignant cutaneous melanoma. Virchows Arch 426:461–467

    Article  CAS  PubMed  Google Scholar 

  • Lebreton L, Annat J, Derrepas P, Dutartre P, Renaut P (1999) Structure-immunosuppressive activity relationships of new analogues of 15-deoxyspergualin. 1. Structural modifications of the hydroxyglycine moiety. J Med Chem 42:277–290

    Article  CAS  PubMed  Google Scholar 

  • Lee JS, Lee JJ, Seo JS (2005) HSP70 deficiency results in activation of c-Jun N-terminal kinase, extracellular signal-regulated kinase, and caspase-3 in hyperosmolarity-induced apoptosis. J Biol Chem 280:6634–6641

    Article  CAS  PubMed  Google Scholar 

  • Lee KJ, Kim YM, Kim DY et al (2006) Release of heat shock protein 70 (Hsp70) and the effects of extracellular Hsp70 on matrix metalloproteinase-9 expression in human monocytic U937 cells. Exp Mol Med 38:364–374

    Article  CAS  PubMed  Google Scholar 

  • Lee JH, Won SM, Suh J et al (2010) Induction of the unfolded protein response and cell death pathway in Alzheimer’s disease, but not in aged Tg2576 mice. Exp Mol Med 42:386–394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lenschow DJ, Lai C, Frias-Staheli N et al (2007) IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses. Proc Natl Acad Sci U S A 104:1371–1376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leu JI, Pimkina J, Frank A, Murphy ME, George DL (2009) A small molecule inhibitor of inducible heat shock protein 70. Mol Cell 36:15–27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leung TK, Rajendran MY, Monfries C, Hall C, Lim L (1990) The human heat-shock protein family. Expression of a novel heat-inducible HSP70 (HSP70B’) and isolation of its cDNA and genomic DNA. Biochem J 267:125–132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Y, Kang X, Wang Q (2011) HSP70 decreases receptor-dependent phosphorylation of Smad2 and blocks TGF-beta-induced epithelial-mesenchymal transition. J Genet Genomics 38:111–116

    Article  PubMed  CAS  Google Scholar 

  • Li X, Srinivasan SR, Connarn J et al. (2013a) Analogs of the allosteric heat shock protein 70 (Hsp70) inhibitor, MKT-077, as anti-cancer agents. ACS Med Chem Lett 4

  • Li Z, Song Y, Xing R et al (2013b) Heat shock protein 70 acts as a potential biomarker for early diagnosis of heart failure. PLoS ONE 8:e67964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li X, Colvin T, Rauch JN et al (2015) Validation of the Hsp70-Bag3 protein-protein interaction as a potential therapeutic target in cancer. Mol Cancer Ther 14:642–648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liebscher M, Jahreis G, Lucke C et al (2007) Fatty acyl benzamido antibacterials based on inhibition of DnaK-catalyzed protein folding. J Biol Chem 282:4437–4446

    Article  CAS  PubMed  Google Scholar 

  • Lindquist S, Craig EA (1988) The heat-shock proteins. Annu Rev Genet 22:631–677

    Article  CAS  PubMed  Google Scholar 

  • MacKenzie TN, Mujumdar N, Banerjee S et al (2013) Triptolide induces the expression of miR-142-3p: a negative regulator of heat shock protein 70 and pancreatic cancer cell proliferation. Mol Cancer Ther 12:1266–1275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Madach K, Molvarec A, Rigo J Jr et al (2008) Elevated serum 70 kDa heat shock protein level reflects tissue damage and disease severity in the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Eur J Obstet Gynecol Reprod Biol 139:133–138

    Article  CAS  PubMed  Google Scholar 

  • Malusecka E, Zborek A, Krzyzowska-Gruca S, Krawczyk Z (2001) Expression of heat shock proteins HSP70 and HSP27 in primary non-small cell lung carcinomas. An immunohistochemical study. Anticancer Res 21:1015–1021

    CAS  PubMed  Google Scholar 

  • Mambula SS, Calderwood SK (2006) Heat shock protein 70 is secreted from tumor cells by a nonclassical pathway involving lysosomal endosomes. J Immunol 177:7849–7857

    Article  CAS  PubMed  Google Scholar 

  • Mamelak D, Lingwood C (2001) The ATPase domain of hsp70 possesses a unique binding specificity for 3′-sulfogalactolipids. J Biol Chem 276:449–456

    Article  CAS  PubMed  Google Scholar 

  • Mao H, Li F, Ruchalski K et al (2003) hsp72 inhibits focal adhesion kinase degradation in ATP-depleted renal epithelial cells. J Biol Chem 278:18214–18220

    Article  CAS  PubMed  Google Scholar 

  • Marotta F, Koike K, Lorenzetti A et al (2007) Nutraceutical strategy in aging: targeting heat shock protein and inflammatory profile through understanding interleukin-6 polymorphism. Ann N Y Acad Sci 1119:196–202

    Article  CAS  PubMed  Google Scholar 

  • Mason PB Jr, Lis JT (1997) Cooperative and competitive protein interactions at the hsp70 promoter. J Biol Chem 272:33227–33233

    Article  CAS  PubMed  Google Scholar 

  • Massey AJ, Williamson DS, Browne H et al (2010) A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells. Cancer Chemother Pharmacol 66:535–545

    Article  CAS  PubMed  Google Scholar 

  • Matokanovic M, Barisic K, Filipovic-Grcic J, Maysinger D (2013) Hsp70 silencing with siRNA in nanocarriers enhances cancer cell death induced by the inhibitor of Hsp90. Eur J Pharm Sci 50:149–158

    Article  CAS  PubMed  Google Scholar 

  • Mattoo RU, Goloubinoff P (2014) Molecular chaperones are nanomachines that catalytically unfold misfolded and alternatively folded proteins. Cell Mol Life Sci 71:3311–3325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mattoo RU, Sharma SK, Priya S, Finka A, Goloubinoff P (2013) Hsp110 is a bona fide chaperone using ATP to unfold stable misfolded polypeptides and reciprocally collaborate with Hsp70 to solubilize protein aggregates. J Biol Chem 288:21399–21411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miyata Y, Rauch JN, Jinwal UK et al (2012) Cysteine reactivity distinguishes redox sensing by the heat-inducible and constitutive forms of heat shock protein 70. Chem Biol 19:1391–1399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miyata Y, Li X, Lee HF et al (2013) Synthesis and initial evaluation of YM-08, a blood–brain barrier permeable derivative of the heat shock protein 70 (Hsp70) inhibitor MKT-077, which reduces tau levels. ACS Chem Neurosci 4:930–939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mizzen LA, Chang C, Garrels JI, Welch WJ (1989) Identification, characterization, and purification of two mammalian stress proteins present in mitochondria, grp 75, a member of the hsp 70 family and hsp 58, a homolog of the bacterial groEL protein. J Biol Chem 264:20664–20675

    CAS  PubMed  Google Scholar 

  • Molvarec A, Prohaszka Z, Nagy B et al (2006) Association of elevated serum heat-shock protein 70 concentration with transient hypertension of pregnancy, preeclampsia and superimposed preeclampsia: a case–control study. J Hum Hypertens 20:780–786

    Article  CAS  PubMed  Google Scholar 

  • Molvarec A, Prohaszka Z, Nagy B et al (2007a) Association of increased serum heat shock protein 70 and C-reactive protein concentrations and decreased serum alpha(2)-HS glycoprotein concentration with the syndrome of hemolysis, elevated liver enzymes, and low platelet count. J Reprod Immunol 73:172–179

    Article  CAS  PubMed  Google Scholar 

  • Molvarec A, Rigo J Jr, Nagy B et al (2007b) Serum heat shock protein 70 levels are decreased in normal human pregnancy. J Reprod Immunol 74:163–169

    Article  CAS  PubMed  Google Scholar 

  • Molvarec A, Tamasi L, Losonczy G et al (2010) Circulating heat shock protein 70 (HSPA1A) in normal and pathological pregnancies. Cell Stress Chaperones 15:237–247

    Article  CAS  PubMed  Google Scholar 

  • Moretta L, Bottino C, Pende D et al (2005) Human natural killer cells: molecular mechanisms controlling NK cell activation and tumor cell lysis. Immunol Lett 100:7–13

    Article  CAS  PubMed  Google Scholar 

  • Multhoff G (2007) Heat shock protein 70 (Hsp70): membrane location, export and immunological relevance. Methods 43:229–237

    Article  CAS  PubMed  Google Scholar 

  • Multhoff G, Hightower LE (1996) Cell surface expression of heat shock proteins and the immune response. Cell Stress Chaperones 1:167–176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Multhoff G, Radons J (2012) Radiation, inflammation, and immune responses in cancer. Front Oncol 2:58. doi:10.3389/fonc.2012.00058

    PubMed  PubMed Central  Google Scholar 

  • Multhoff G, Botzler C, Wiesnet M et al (1995) A stress-inducible 72-kDa heat-shock protein (HSP72) is expressed on the surface of human tumor cells, but not on normal cells. Int J Cancer 61:272–279

    Article  CAS  PubMed  Google Scholar 

  • Multhoff G, Botzler C, Jennen L et al (1997) Heat shock protein 72 on tumor cells: a recognition structure for natural killer cells. J Immunol 158:4341–4350

    CAS  PubMed  Google Scholar 

  • Multhoff G, Mizzen L, Winchester CC et al (1999) Heat shock protein 70 (Hsp70) stimulates proliferation and cytolytic activity of natural killer cells. Exp Hematol 27:1627–1636

    Article  CAS  PubMed  Google Scholar 

  • Multhoff G, Pfister K, Gehrmann M et al (2001) A 14-mer Hsp70 peptide stimulates natural killer (NK) cell activity. Cell Stress Chaperones 6:337–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Multhoff G, Pockley AG, Streffer C, Gaipl US (2012) Dual role of heat shock proteins (HSPs) in anti-tumor immunity. Curr Mol Med 12:1174–1182

    Article  CAS  PubMed  Google Scholar 

  • Multhoff G, Pockley AG, Schmid TE, Schilling D (2015) The role of heat shock protein 70 (Hsp70) in radiation-induced immunomodulation. Cancer Lett 368:179–184

    Article  CAS  PubMed  Google Scholar 

  • Munro S, Pelham HR (1987) A C-terminal signal prevents secretion of luminal ER proteins. Cell 48:899–907

    Article  CAS  PubMed  Google Scholar 

  • Murakami N, Kuhnel A, Schmid TE et al (2015) Role of membrane Hsp70 in radiation sensitivity of tumor cells. Radiat Oncol 10:149

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Murshid A, Gong J, Stevenson MA, Calderwood SK (2011) Heat shock proteins and cancer vaccines: developments in the past decade and chaperoning in the decade to come. Expert Rev Vaccines 10:1553–1568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nadler SG, Dischino DD, Malacko AR et al (1998) Identification of a binding site on Hsc70 for the immunosuppressant 15-deoxyspergualin. Biochem Biophys Res Commun 253:176–180

    Article  CAS  PubMed  Google Scholar 

  • Nakachi K, Matsuyama S, Miyake S, Suganuma M, Imai K (2000) Preventive effects of drinking green tea on cancer and cardiovascular disease: epidemiological evidence for multiple targeting prevention. Biofactors 13:49–54

    Article  CAS  PubMed  Google Scholar 

  • Nakhjavani M, Morteza A, Khajeali L et al (2010) Increased serum HSP70 levels are associated with the duration of diabetes. Cell Stress Chaperones 15:959–964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nambiar D, Rajamani P, Singh RP (2011) Effects of phytochemicals on ionization radiation-mediated carcinogenesis and cancer therapy. Mutat Res 728:139–157

    Article  CAS  PubMed  Google Scholar 

  • Njemini R, Bautmans I, Onyema OO et al (2011) Circulating heat shock protein 70 in health, aging and disease. BMC Immunol 12:24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nuss JE, Choksi KB, DeFord JH, Papaconstantinou J (2008) Decreased enzyme activities of chaperones PDI and BiP in aged mouse livers. Biochem Biophys Res Commun 365:355–361

    Article  CAS  PubMed  Google Scholar 

  • Nylandsted J, Rohde M, Brand K et al (2000) Selective depletion of heat shock protein 70 (Hsp70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2. Proc Natl Acad Sci U S A 97:7871–7876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nylandsted J, Gyrd-Hansen M, Danielewicz A et al (2004) Heat shock protein 70 promotes cell survival by inhibiting lysosomal membrane permeabilization. J Exp Med 200:425–435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O’Leary JC III, Li Q, Marinec P et al (2010) Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden. Mol Neurodegener 5:45

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ostorhazi E, Voros E, Nemes-Nikodem E et al (2013) Rapid systemic and local treatments with the antibacterial peptide dimer A3-APO and its monomeric metabolite eliminate bacteria and reduce inflammation in intradermal lesions infected with Propionibacterium acnes and meticillin-resistant Staphylococcus aureus. Int J Antimicrob Agents 42:537–543

    Article  CAS  PubMed  Google Scholar 

  • Otaka M, Yamamoto S, Ogasawara K et al (2007) The induction mechanism of the molecular chaperone HSP70 in the gastric mucosa by Geranylgeranylacetone (HSP-inducer). Biochem Biophys Res Commun 353:399–404

    Article  CAS  PubMed  Google Scholar 

  • Otterson GA, Flynn GC, Kratzke RA et al (1994) Stch encodes the ‘ATPase core’ of a microsomal stress 70 protein. EMBO J 13:1216–1225

    CAS  PubMed  PubMed Central  Google Scholar 

  • Otvos L Jr, O I, Rogers ME et al (2000) Interaction between heat shock proteins and antimicrobial peptides. Biochemistry 39:14150–14159

    Article  CAS  PubMed  Google Scholar 

  • Otvos L Jr, Wade JD, Lin F et al (2005) Designer antibacterial peptides kill fluoroquinolone-resistant clinical isolates. J Med Chem 48:5349–5359

    Article  CAS  PubMed  Google Scholar 

  • Otvos L, Flick-Smith H, Fox M et al (2014) The designer proline-rich antibacterial peptide A3-APO prevents Bacillus anthracis mortality by deactivating bacterial toxins. Protein Pept Lett 21:374–381

    Article  CAS  PubMed  Google Scholar 

  • Ouyang YB, Giffard RG (2013) MicroRNAs regulate the chaperone network in cerebral ischemia. Transl Stroke Res 4:693–703

    Article  CAS  PubMed  Google Scholar 

  • Paduch R, Jakubowicz-Gil J, Kandefer-Szerszen M (2009) Expression of HSP27, HSP72 and MRP proteins in in vitro co-culture of colon tumour cell spheroids with normal cells after incubation with rhTGF-beta1 and/or CPT-11. J Biosci 34:927–940

    Article  CAS  PubMed  Google Scholar 

  • Pagetta A, Folda A, Brunati AM, Finotti P (2003) Identification and purification from the plasma of type 1 diabetic subjects of a proteolytically active Grp94. Evidence that Grp94 is entirely responsible for plasma proteolytic activity. Diabetologia 46:996–1006

    Article  CAS  PubMed  Google Scholar 

  • Park HJ, Mylvaganum M, McPherson A et al (2009) A soluble sulfogalactosyl ceramide mimic promotes Delta F508 CFTR escape from endoplasmic reticulum associated degradation. Chem Biol 16:461–470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peng C, Yang P, Cui Y et al (2013) HSPA9 overexpression inhibits apoptin-induced apoptosis in the HepG2 cell line. Oncol Rep 29:2431–2437

    CAS  PubMed  Google Scholar 

  • Pfister K, Radons J, Busch R et al (2007) Patient survival by Hsp70 membrane phenotype: association with different routes of metastasis. Cancer 110:926–935

    Article  PubMed  Google Scholar 

  • Pirkkala L, Nykanen P, Sistonen L (2001) Roles of the heat shock transcription factors in regulation of the heat shock response and beyond. FASEB J 15:1118–1131

    Article  CAS  PubMed  Google Scholar 

  • Plowman J, Harrison SD Jr, Trader MW et al (1987) Preclinical antitumor activity and pharmacological properties of deoxyspergualin. Cancer Res 47:685–689

    CAS  PubMed  Google Scholar 

  • Pocaly M, Lagarde V, Etienne G et al (2007) Overexpression of the heat-shock protein 70 is associated to imatinib resistance in chronic myeloid leukemia. Leukemia 21:93–101

    Article  CAS  PubMed  Google Scholar 

  • Pockley AG, Shepherd J, Corton JM (1998) Detection of heat shock protein 70 (Hsp70) and anti-Hsp70 antibodies in the serum of normal individuals. Immunol Invest 27:367–377

    Article  CAS  PubMed  Google Scholar 

  • Pockley AG, Bulmer J, Hanks BM, Wright BH (1999) Identification of human heat shock protein 60 (Hsp60) and anti-Hsp60 antibodies in the peripheral circulation of normal individuals. Cell Stress Chaperones 4:29–35

    Article  CAS  PubMed  Google Scholar 

  • Pockley AG, Muthana M, Calderwood SK (2008) The dual immunoregulatory roles of stress proteins. Trends Biochem Sci 33:71–79

    Article  CAS  PubMed  Google Scholar 

  • Pockley AG, Henderson B, Multhoff G (2014) Extracellular cell stress proteins as biomarkers of human disease. Biochem Soc Trans 42:1744–1751

    Article  CAS  PubMed  Google Scholar 

  • Propper DJ, Braybrooke JP, Taylor DJ et al (1999) Phase I trial of the selective mitochondrial toxin MKT077 in chemo-resistant solid tumours. Ann Oncol 10:923–927

    Article  CAS  PubMed  Google Scholar 

  • Qu B, Jia Y, Liu Y et al (2015) The detection and role of heat shock protein 70 in various nondisease conditions and disease conditions: a literature review. Cell Stress Chaperones 20:885–892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rappa F, Farina F, Zummo G et al (2012) HSP-molecular chaperones in cancer biogenesis and tumor therapy: an overview. Anticancer Res 32:5139–5150

    CAS  PubMed  Google Scholar 

  • Ravagnan L, Gurbuxani S, Susin SA et al (2001) Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nat Cell Biol 3:839–843

    Article  CAS  PubMed  Google Scholar 

  • Rea IM, McNerlan S, Pockley AG (2001) Serum heat shock protein and anti-heat shock protein antibody levels in aging. Exp Gerontol 36:341–352

    Article  CAS  PubMed  Google Scholar 

  • Rerole AL, Gobbo J, De TA et al (2011) Peptides and aptamers targeting HSP70: a novel approach for anticancer chemotherapy. Cancer Res 71:484–495

    Article  CAS  PubMed  Google Scholar 

  • Ritossa F (1962) A new puffing pattern induced by temperature shock and DNP in Drosophila. Experientia 18:571–573

    Article  CAS  Google Scholar 

  • Rohde M, Daugaard M, Jensen MH et al (2005) Members of the heat-shock protein 70 family promote cancer cell growth by distinct mechanisms. Genes Dev 19:570–582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roufayel R, Johnston DS, Mosser DD (2014) The elimination of miR-23a in heat-stressed cells promotes NOXA-induced cell death and is prevented by HSP70. Cell Death Dis 5:e1546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rousaki A, Miyata Y, Jinwal UK et al (2011) Allosteric drugs: the interaction of antitumor compound MKT-077 with human Hsp70 chaperones. J Mol Biol 411:614–632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rozgonyi F, Szabo D, Kocsis B et al (2009) The antibacterial effect of a proline-rich antibacterial peptide A3-APO. Curr Med Chem 16:3996–4002

    Article  CAS  PubMed  Google Scholar 

  • Rutkowski DT, Kaufman RJ (2004) A trip to the ER: coping with stress. Trends Cell Biol 14:20–28

    Article  CAS  PubMed  Google Scholar 

  • Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133:775–787

    Article  CAS  PubMed  Google Scholar 

  • Sandström ME, Siegler JC, Lovell RJ, Madden LA, McNaughton L (2008) The effect of 15 consecutive days of heat-exercise acclimation on heat shock protein 70. Cell Stress Chaperones 13:169–175

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Santarosa M, Favaro D, Quaia M, Galligioni E (1997) Expression of heat shock protein 72 in renal cell carcinoma: possible role and prognostic implications in cancer patients. Eur J Cancer 33:873–877

    Article  CAS  PubMed  Google Scholar 

  • Schilling D, Gehrmann M, Steinem C et al (2009) Binding of heat shock protein 70 to extracellular phosphatidylserine promotes killing of normoxic and hypoxic tumor cells. FASEB J 23:2467–2477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schlecht R, Scholz SR, Dahmen H et al (2013) Functional analysis of Hsp70 inhibitors. PLoS ONE 8:e78443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmitt E, Parcellier A, Gurbuxani S et al (2003) Chemosensitization by a non-apoptogenic heat shock protein 70-binding apoptosis-inducing factor mutant. Cancer Res 63:8233–8240

    CAS  PubMed  Google Scholar 

  • Schmitt E, Maingret L, Puig PE et al (2006) Heat shock protein 70 neutralization exerts potent antitumor effects in animal models of colon cancer and melanoma. Cancer Res 66:4191–4197

    Article  CAS  PubMed  Google Scholar 

  • Schuermann JP, Jiang J, Cuellar J et al (2008) Structure of the Hsp110:Hsc70 nucleotide exchange machine. Mol Cell 31:232–243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shamovsky I, Nudler E (2008) New insights into the mechanism of heat shock response activation. Cell Mol Life Sci 65:855–861

    Article  CAS  PubMed  Google Scholar 

  • Sharma SK, De Los RP, Christen P, Lustig A, Goloubinoff P (2010) The kinetic parameters and energy cost of the Hsp70 chaperone as a polypeptide unfoldase. Nat Chem Biol 6:914–920

    Article  CAS  PubMed  Google Scholar 

  • Shevtsov MA, Nikolaev BP, Yakovleva LY et al. (2015) 70-kDa heat shock protein coated magnetic nanocarriers as a nanovaccine for induction of anti-tumor immune response in experimental glioma. J Control Release

  • Shimizu M, Fukutomi Y, Ninomiya M et al (2008) Green tea extracts for the prevention of metachronous colorectal adenomas: a pilot study. Cancer Epidemiol Biomarkers Prev 17:3020–3025

    Article  CAS  PubMed  Google Scholar 

  • Shiozaki H, Doki Y, Kawanishi K et al (2000) Clinical application of malignancy potential grading as a prognostic factor of human esophageal cancers. Surgery 127:552–561

    Article  CAS  PubMed  Google Scholar 

  • Shomura Y, Dragovic Z, Chang HC et al (2005) Regulation of Hsp70 function by HspBP1: structural analysis reveals an alternate mechanism for Hsp70 nucleotide exchange. Mol Cell 17:367–379

    CAS  PubMed  Google Scholar 

  • Siddiqui F, Avery PR, Li CY et al (2008) Induction of the human heat shock promoter HSP70B by nutritional stress: implications for cancer gene therapy. Cancer Invest 26:553–561

    Article  CAS  PubMed  Google Scholar 

  • Singh-Jasuja H, Toes RE, Spee P et al (2000) Cross-presentation of glycoprotein 96-associated antigens on major histocompatibility complex class I molecules requires receptor-mediated endocytosis. J Exp Med 191:1965–1974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smyth MJ, Cretney E, Takeda K et al (2001) Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) contributes to interferon gamma-dependent natural killer cell protection from tumor metastasis. J Exp Med 193:661–670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Specht HM, Ahrens N, Blankenstein C et al (2015) Heat shock protein 70 (Hsp70) peptide activated natural killer (NK) cells for the treatment of patients with non-small cell lung cancer (NSCLC) after radiochemotherapy (RCTx)—from preclinical studies to a clinical phase II trial. Front Immunol 6:162

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Srivastava PK (2005) Immunotherapy for human cancer using heat shock protein-peptide complexes. Curr Oncol Rep 7:104–108

    Article  CAS  PubMed  Google Scholar 

  • Stangl S, Gehrmann M, Riegger J et al (2011) Targeting membrane heat-shock protein 70 (Hsp70) on tumors by cmHsp70.1 antibody. Proc Natl Acad Sci U S A 108:733–738

    Article  CAS  PubMed  Google Scholar 

  • Stankiewicz AR, Lachapelle G, Foo CP, Radicioni SM, Mosser DD (2005) Hsp70 inhibits heat-induced apoptosis upstream of mitochondria by preventing Bax translocation. J Biol Chem 280:38729–38739

    Article  CAS  PubMed  Google Scholar 

  • Steele AJ, Prentice AG, Hoffbrand AV et al (2009) 2-Phenylacetylenesulfonamide (PAS) induces p53-independent apoptotic killing of B-chronic lymphocytic leukemia (CLL) cells. Blood 114:1217–1225

    Article  CAS  PubMed  Google Scholar 

  • Stephanou A, Latchman DS (2005) Opposing actions of STAT-1 and STAT-3. Growth Factors 23:177–182

    Article  CAS  PubMed  Google Scholar 

  • Stephanou A, Isenberg DA, Nakajima K, Latchman DS (1999) Signal transducer and activator of transcription-1 and heat shock factor-1 interact and activate the transcription of the Hsp-70 and Hsp-90beta gene promoters. J Biol Chem 274:1723–1728

    Article  CAS  PubMed  Google Scholar 

  • Stocki P, Wang XN, Dickinson AM (2012) Inducible heat shock protein 70 reduces T cell responses and stimulatory capacity of monocyte-derived dendritic cells. J Biol Chem 287:12387–12394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun XF, Zhang H, Carstensen J, Jansson A, Nordenskjold B (1997) Heat shock protein 72/73 in relation to cytoplasmic p53 expression and prognosis in colorectal adenocarcinomas. Int J Cancer 74:600–604

    Article  CAS  PubMed  Google Scholar 

  • Suzuki H, Noguchi S, Arakawa H et al (2010) Peptide-binding sites as revealed by the crystal structures of the human Hsp40 Hdj1 C-terminal domain in complex with the octapeptide from human Hsp70. Biochemistry 49:8577–8584

    Article  CAS  PubMed  Google Scholar 

  • Suzuki M, Iwasaki M, Sugio A et al (2011) BAG3 (BCL2-associated athanogene 3) interacts with MMP-2 to positively regulate invasion by ovarian carcinoma cells. Cancer Lett 303:65–71

    Article  CAS  PubMed  Google Scholar 

  • Svitalkova T, Remakova M, Plestilova L et al (2014) A3.30 Plasma level of HSP70 protein is increased in Czech patients with idiopathic inflammatory myopathy. Ann Rheum Dis 73(Suppl 1):A54

    Article  Google Scholar 

  • Syrigos KN, Harrington KJ, Karayiannakis AJ et al (2003) Clinical significance of heat shock protein-70 expression in bladder cancer. Urology 61:677–680

    Article  PubMed  Google Scholar 

  • Takayama S, Xie Z, Reed JC (1999) An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators. J Biol Chem 274:781–786

    Article  CAS  PubMed  Google Scholar 

  • Teng Y, Ngoka L, Mei Y, Lesoon L, Cowell JK (2012) HSP90 and HSP70 proteins are essential for stabilization and activation of WASF3 metastasis-promoting protein. J Biol Chem 287:10051–10059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Terry DF, McCormick M, Andersen S et al (2004) Cardiovascular disease delay in centenarian offspring: role of heat shock proteins. Ann N Y Acad Sci 1019:502–505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Theriault JR, Adachi H, Calderwood SK (2006) Role of scavenger receptors in the binding and internalization of heat shock protein 70. J Immunol 177:8604–8611

    Article  CAS  PubMed  Google Scholar 

  • Thomas X, Campos L, Mounier C et al (2005) Expression of heat-shock proteins is associated with major adverse prognostic factors in acute myeloid leukemia. Leuk Res 29:1049–1058

    Article  CAS  PubMed  Google Scholar 

  • Tissieres A, Mitchell HK, Tracy UM (1974) Protein synthesis in salivary glands of Drosophila melanogaster: relation to chromosome puffs. J Mol Biol 84:389–398

    Article  CAS  PubMed  Google Scholar 

  • Trieb K, Lechleitner T, Lang S et al (1998) Heat shock protein 72 expression in osteosarcomas correlates with good response to neoadjuvant chemotherapy. Hum Pathol 29:1050–1055

    Article  CAS  PubMed  Google Scholar 

  • Tsan MF, Gao B (2004) Heat shock protein and innate immunity. Cell Mol Immunol 1:274–279

    CAS  PubMed  Google Scholar 

  • Tu J, Liao J, Luk AC et al (2015) MicroRNAs mediated targeting on the Yin-yang dynamics of DNA methylation in disease and development. Int J Biochem Cell Biol 67:115–120

    Article  CAS  PubMed  Google Scholar 

  • Tzankov S, Wong MJ, Shi K, Nassif C, Young JC (2008) Functional divergence between co-chaperones of Hsc70. J Biol Chem 283:27100–27109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vabulas, R.M., and Wagner, H. (2005). Toll-like receptor-dependent activation of antigen presenting cells by Hsp60, gp96 and Hsp70. In: Molecular chaperones and cell signalling, eds. B. Henderson and A. G. Pockley (New York, Cambridge University Press), 113–132

  • Vega VL, Rodriguez-Silva M, Frey T et al (2008) Hsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages. J Immunol 180:4299–4307

    Article  CAS  PubMed  Google Scholar 

  • Wachstein J, Tischer S, Figueiredo C et al (2012) HSP70 enhances immunosuppressive function of CD4(+)CD25(+)FoxP3(+) T regulatory cells and cytotoxicity in CD4(+)CD25(−) T cells. PLoS ONE 7:e51747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wadhwa R, Sugihara T, Yoshida A et al (2000) Selective toxicity of MKT-077 to cancer cells is mediated by its binding to the hsp70 family protein mot-2 and reactivation of p53 function. Cancer Res 60:6818–6821

    CAS  PubMed  Google Scholar 

  • Wallin RP, Lundqvist A, More SH et al (2002) Heat-shock proteins as activators of the innate immune system. Trends Immunol 23:130–135

    Article  CAS  PubMed  Google Scholar 

  • Walsh N, Larkin A, Swan N et al (2011) RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation. Cancer Lett 306:180–189

    Article  CAS  PubMed  Google Scholar 

  • Wan T, Zhou X, Chen G et al (2004) Novel heat shock protein Hsp70L1 activates dendritic cells and acts as a Th1 polarizing adjuvant. Blood 103:1747–1754

    Article  CAS  PubMed  Google Scholar 

  • Wang AM, Morishima Y, Clapp KM et al (2010) Inhibition of hsp70 by methylene blue affects signaling protein function and ubiquitination and modulates polyglutamine protein degradation. J Biol Chem 285:15714–15723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weng D, Song B, Durfee J et al (2011) Induction of cytotoxic T lymphocytes against ovarian cancer-initiating cells. Int J Cancer 129:1990–2001

    Article  CAS  PubMed  Google Scholar 

  • Weng D, Song B, Koido S, Calderwood SK, Gong J (2013) Immunotherapy of radioresistant mammary tumors with early metastasis using molecular chaperone vaccines combined with ionizing radiation. J Immunol 191:755–763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Westerheide SD, Anckar J, Stevens SM Jr, Sistonen L, Morimoto RI (2009) Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science 323:1063–1066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Westwood JT, Clos J, Wu C (1991) Stress-induced oligomerization and chromosomal relocalization of heat-shock factor. Nature 353:822–827

    Article  CAS  PubMed  Google Scholar 

  • Whetstone H, Lingwood C (2003) 3′Sulfogalactolipid binding specifically inhibits Hsp70 ATPase activity in vitro. Biochemistry 42:1611–1617

    Article  CAS  PubMed  Google Scholar 

  • Wigmore SJ, Sangster K, McNally SJ et al (2007) De-repression of heat shock transcription factor-1 in interleukin-6-treated hepatocytes is mediated by downregulation of glycogen synthase kinase 3beta and MAPK/ERK-1. Int J Mol Med 19:413–420

    CAS  PubMed  Google Scholar 

  • Williams DR, Ko SK, Park S, Lee MR, Shin I (2008) An apoptosis-inducing small molecule that binds to heat shock protein 70. Angew Chem Int Ed Engl 47:7466–7469

    Article  CAS  PubMed  Google Scholar 

  • Williamson DS, Borgognoni J, Clay A et al (2009) Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design. J Med Chem 52:1510–1513

    Article  CAS  PubMed  Google Scholar 

  • Wischik CM, Betham P, Wischik DJ, Seng KM (2008) Tau aggregation inhibitor (TAI) therapy with Rember™ arrests disease progression in mild and moderate Alzheimer’s disease over 50 weeks. Alzheimers Dement 4:T167

    Article  Google Scholar 

  • Wright CM, Seguin SP, Fewell SW et al (2009) Inhibition of simian virus 40 replication by targeting the molecular chaperone function and ATPase activity of T antigen. Virus Res 141:71–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu G, Osada M, Guo Z et al (2005) DeltaNp63alpha up-regulates the Hsp70 gene in human cancer. Cancer Res 65:758–766

    CAS  PubMed  Google Scholar 

  • Wu CY, Lin CT, Wu MZ, Wu KJ (2011) Induction of HSPA4 and HSPA14 by NBS1 overexpression contributes to NBS1-induced in vitro metastatic and transformation activity. J Biomed Sci 18:1

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Xia C, Cai Y, Lin Y et al. (2015) MiR-133b-5p regulates the expression of the heat shock protein 70 during rat neuronal cell apoptosis induced by the gp120 V3 loop peptide. J Med Virol

  • Xin L, Li X, Deng H et al (2012) Development of stable HSPA1A promoter-driven luciferase reporter HepG2 cells for assessing the toxicity of organic pollutants present in air. Cell Stress Chaperones 17:567–576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yaglom JA, Gabai VL, Sherman MY (2007) High levels of heat shock protein Hsp72 in cancer cells suppress default senescence pathways. Cancer Res 67:2373–2381

    Article  CAS  PubMed  Google Scholar 

  • Yang H, Chen G, Kanai N et al (2003) Monotherapy with LF 15-0195, an analogue of 15-deoxyspergualin, significantly prolongs renal allograft survival in monkeys. Transplantation 75:1166–1171

    Article  CAS  PubMed  Google Scholar 

  • Yang CS, Lambert JD, Ju J, Lu G, Sang S (2007) Tea and cancer prevention: molecular mechanisms and human relevance. Toxicol Appl Pharmacol 224:265–273

    Article  CAS  PubMed  Google Scholar 

  • Yang X, Wang J, Zhou Y et al (2012) Hsp70 promotes chemoresistance by blocking Bax mitochondrial translocation in ovarian cancer cells. Cancer Lett 321:137–143

    Article  CAS  PubMed  Google Scholar 

  • Yang Z, Zhuang L, Szatmary P et al (2015) Upregulation of heat shock proteins (HSPA12A, HSP90B1, HSPA4, HSPA5 and HSPA6) in tumour tissues is associated with poor outcomes from HBV-related early-stage hepatocellular carcinoma. Int J Med Sci 12:256–263

    Article  PubMed  PubMed Central  Google Scholar 

  • Yin C, Salloum FN, Kukreja RC (2009) A novel role of microRNA in late preconditioning: upregulation of endothelial nitric oxide synthase and heat shock protein 70. Circ Res 104:572–575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yiu CC, Chanplakorn N, Chan MS et al (2010) Down-regulation of heat-shock protein 70 (HSP-70) correlated with responsiveness to neoadjuvant aromatase inhibitor therapy in breast cancer patients. Anticancer Res 30:3465–3472

    CAS  PubMed  Google Scholar 

  • Zhang Z, Cheng Y (2014) miR-16-1 promotes the aberrant alpha-synuclein accumulation in parkinson disease via targeting heat shock protein 70. Scientific World J 2014:938348

    Google Scholar 

  • Zhu X, Zhao X, Burkholder WF et al (1996) Structural analysis of substrate binding by the molecular chaperone DnaK. Science 272:1606–1614

    Article  CAS  PubMed  Google Scholar 

  • Zhu D, Dix DJ, Eddy EM (1997) HSP70-2 is required for CDC2 kinase activity in meiosis I of mouse spermatocytes. Development 124:3007–3014

    CAS  PubMed  Google Scholar 

  • Zhuravleva A, Clerico EM, Gierasch LM (2012) An interdomain energetic tug-of-war creates the allosterically active state in Hsp70 molecular chaperones. Cell 151:1296–1307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The author wants to thank A. Graham Pockley, Nottingham Trent University, UK, for critical reading of the manuscript and his helpful comments.

Author information

Authors and Affiliations

  1. Scientific Consulting International, Mühldorfer Str. 64, 84503, Altötting, Germany

    Jürgen Radons

Authors
  1. Jürgen Radons
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jürgen Radons.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Radons, J. The human HSP70 family of chaperones: where do we stand?. Cell Stress and Chaperones 21, 379–404 (2016). https://doi.org/10.1007/s12192-016-0676-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12192-016-0676-6

Keywords

Search

Navigation