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Changes in the regulation of heat shock gene expression in neuronal cell differentiation

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Cell Stress and Chaperones Aims and scope

Abstract

Neuronal differentiation of the NG108-15 neuroblastoma–glioma hybrid cells is accompanied by a marked attenuation in the heat shock induction of the Hsp70-firefly luciferase reporter gene activity. Analysis of the amount and activation of heat shock factor 1, induction of mRNAhsp, and the synthesis and accumulation of heat shock proteins (HSPs) in the undifferentiated and differentiated cells suggest a transcriptional mechanism for this attenuation. Concomitant with a decreased induction of the 72-kDa Hsp70 protein in the differentiated cells, there is an increased abundance of the constitutive 73-kDa Hsc70, a protein known to function in vesicle trafficking. Assessment of sensitivity of the undifferentiated and differentiated cells against stress-induced cell death reveals a significantly greater vulnerability of the differentiated cells toward the cytotoxic effects of arsenite and glutamate/glycine. This study shows that changes in regulation of the HSP and HSC proteins are components of the neuronal cell differentiation program and that the attenuated induction of HSPs likely contributes to neuronal vulnerability whereas the increased expression of Hsc70 likely has a role in neural-specific functions.

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References

  • Akbar MT, Lundberg AMC, Liu K et al (2003) The neuroprotective effects of heat shock protein 27 overexpression in transgenic animals against kainate-induced seizures and hippocampal cell death. J Biol Chem 278:19956–19965

    Article  PubMed  CAS  Google Scholar 

  • Amin V, Cumming DVE, Latchman DS (1996) Over-expression of heat shock protein 70 protects neuronal cells against both thermal and ischaemic stress but with different efficiencies. Neuro Lett 206:45–48

    Article  CAS  Google Scholar 

  • Batulan Z, Shinder GA, Minotti, S, He BP, Doroudchi MM, Nalbantoglu J, Strong, MJ, Durham HD (2003) High threshold for induction of the stress response in motor neurons is associated with failure to activate HSF1. J Neuroscience 23:5789–5798

    CAS  Google Scholar 

  • Beczkowska IW, Buck J, Inturrisi CE (1996) Retinoic acid-induced increase in delta-opioid receptor and N-methyl-d-aspartate receptor mRNA levels in neuroblastoma × glioma (NG108-15) cells. Brain Res Bull 39:193–199

    Article  PubMed  CAS  Google Scholar 

  • Beczkowska IW, Gracy KN, Pickel VM, Inturrisi CE (1997) Detection of delta opiod receptor and N-methyl-d-aspartate receptor like immunoreactivity in retinoic acid-differentiated neuroblastoma × glioma (NG108-15) cells. J Neurosci Res 47:83–89

    Article  PubMed  CAS  Google Scholar 

  • Benn SC, Brown RH (2004) Putting the heat on ALS. Nat Med 10:345–347

    Article  PubMed  CAS  Google Scholar 

  • Bonini NM (2002) Chaperoning brain degeneration. Proc Natl Acad Sci U S A 99:16407–16411

    Article  PubMed  CAS  Google Scholar 

  • Chen S, Brown IR (2007) Neuronal expression of constitutive heat shock proteins: implications for neurodegenerative diseases. Cell Stress Chaperones 12:51–58

    Article  PubMed  CAS  Google Scholar 

  • Chiti Z, Teschemacher AG (2007) Exocytosis of norepinephrine at axon varicosities and neuronal cell bodies in the rat brain. FASEB J 21:1–11

    Article  Google Scholar 

  • Choi HS, Li B, Lin Z, Huang LE, Liu AY-C (1991) cAMP- and cAMP-dependent protein kinase regulate the human heat shock protein 70 gene promoter activity. J Biol Chem 266:11858–11865

    PubMed  CAS  Google Scholar 

  • Cooper RL, Marin L, Atwood HL (1995) Synaptic differentiation of a single motor neuron: conjoint definition of transmitter release, presynaptic calcium signals, and ultrastructure. J Neurosci 15:4209–4222

    PubMed  CAS  Google Scholar 

  • Dwyer DS, Liu Y, Miao S, Bradley RJ (1996) Neuronal differentiation in PC12 cells is accompanied by diminished inducibility of Hsp70 and HPS 60 in response to heat and ethanol. Neurochemical Res 21:659–666

    Article  CAS  Google Scholar 

  • Feige U, Morimoto RI, Yahara I, Polla BS (eds) (1996) Stress-inducible cellular responses. Birkhauser, Basel

  • Gabai VL, Sherman MY (2002) Interplay between molecular chaperones and signaling pathways in survival of heat shock. J Appl Physiol 92:1742–1748

    Google Scholar 

  • Guzhova I, Kislyakova K, Moskaliova O, Friedlanskaya I, Tytell M, Cheetham M, Margulis V (2001) In vitro studies show that Hsp70 can be released by glia and that exogenous Hsp70 can enhance neuronal stress tolerance. Brain Res 914:66–73

    Article  PubMed  CAS  Google Scholar 

  • Hatayama T, Takahashi H, Yamagishi N (1997) Reduced induction of Hsp70 in PC12 cells during neuronal differentiation. J Biochem 122:904–910

    PubMed  CAS  Google Scholar 

  • Hendrick JP, Hartl FU (1995) The role of molecular chaperones in protein folding. FEBS J 9:1559–1569

    CAS  Google Scholar 

  • Hickey E, Brandon SE, Potter R, Stein G, Stein J, Weber LA (1986) Sequence and organization of genes encoding the human 27 kDa heat shock protein. Nucleic Acids Res 14:4127–4145

    Article  PubMed  CAS  Google Scholar 

  • Huang LE, Zhang H, Bae SW, Liu AY-C (1994) Thiol reducing reagents inhibit the heat shock response: involvement of a redox mechanism in the heat shock signal transduction pathway. J Biol Chem 269:30718–30725

    PubMed  CAS  Google Scholar 

  • Khalil S, Luciano J, Chen W, Liu, AYC (2006) Dynamic regulation and involvement of the heat shock transcriptional response in arsenic carcinogenesis. J Cell Physiol 207:562–569

    Article  PubMed  CAS  Google Scholar 

  • Landsbury PT (2004) Back to the future: the ‘old-fashioned’ way to new medications for neurodegeneration. Nat Rev Neurosci 5:S51–S57

    Article  Google Scholar 

  • Lis J, Wu C (1993) Protein traffic on the heat shock promoter: parking, stalling, and trucking along. Cell 74:1–4

    Article  PubMed  CAS  Google Scholar 

  • Macieira-Coelho A (1995) The last mitoses of the human fibroblast proliferative life span, physiopathologic implications. Mech Ageing Dev 82:91–104

    Article  PubMed  CAS  Google Scholar 

  • Magby JP, Bi C, Chen ZY, Lee FS, Plummer MR (2006) Single-cell characterization of retrograde signaling by brain-derived neurotrophic factor. J Neuroscience 26:13531–13536

    Article  CAS  Google Scholar 

  • Mandell JW, MacLeish PR, Townes-Anderson E (1993) Process outgrowth and synaptic varicosity formation by adult photoreceptors in vitro. J Neuroscience 13:3533–3548

    CAS  Google Scholar 

  • Manzerra P, Brown IR (1996) The neuronal stress response: nuclear translocation of heat shock proteins as an indicator of hyperthermic stress. Exp Cell Res 229:35–47

    Article  PubMed  CAS  Google Scholar 

  • Marcuccilli CJ, Mathur SK, Morimoto RI, Miller RJ (1996) Regulatory differences in the stress response of hippocampal neurons and glial cells after heat shock. J Neuroscience 16:478–485

    CAS  Google Scholar 

  • Meyer SA, Lin A, Liu AYC (1988) Neurite extension and increased expression of R1 cyclic AMP-binding protein in ouabain-resistant neuroblastoma mutants. J Neurochem 51:950–959

    Article  PubMed  CAS  Google Scholar 

  • Michaelis EK (1998) Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging. Prog Neurobiol 54:369–415

    Article  PubMed  CAS  Google Scholar 

  • Morimoto RI (1993) Cells in stress: transcriptional activation of heat shock genes. Science 259:1409–1410

    Article  PubMed  CAS  Google Scholar 

  • Morimoto RI (1998) Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes Dev 12:378–3796

    Article  Google Scholar 

  • Morimoto RI (2006) Stress, aging, and neurodegenerative disease. N Eng J Med 355:2254–2255

    Article  CAS  Google Scholar 

  • Morimoto RI, Tissieres A, Georgopoulos C (eds) (1994) The biology of heat shock proteins and molecular chaperones. Cold Spring Harbor Laboratory Press, New York

  • Mosser DD, Carbon AE, Bourget L, Merlin AB, Sherman MY, Morimoto RI, Massie B (2000) The chaperone function of Hsp70 is required for protection against stress-induced apoptosis. Mol Cell Biol 20:7146–7159

    Article  PubMed  CAS  Google Scholar 

  • Muchowski PJ (2002) Protein misfolding, amyloid formation, and neurodegeneration: a critical role for molecular chaperones? Neuron 35:9–12

    Article  PubMed  CAS  Google Scholar 

  • Muchowski PJ, Wacker JL (2005) Modulation of neurodegeneration by molecular chaperones. Nat Rev Neurosci 6:11–22

    Article  PubMed  CAS  Google Scholar 

  • Nelson P, Christian C, Nirenberg M (1976) Synapse formation between clonal neuroblastoma × glioma hybrid cells and striated muscle cells. Proc Natl Acad Sci U S A 73:123–127

    Article  PubMed  CAS  Google Scholar 

  • Nirenberg M, Wilson S, Higashida H et al (1983) Synapse formation by neuroblastoma hybrid cells. Cold Spring Harbor Symp Quant Biol 48:707–715

    PubMed  CAS  Google Scholar 

  • Nirenberg M, Wilson S, Higashida H et al (1984) Modulation of synapse formation by cyclic adenosine monophsophate. Science 222:794–799

    Article  Google Scholar 

  • Nishimura RN, Dwyer BE (1996) Evidence for different mechanisms of induction of Hsp70i: a comparison of cultured rat cortical neurons with astrocytes. Mol Brain Res 36:227–239

    Article  PubMed  CAS  Google Scholar 

  • Pizzi M, Boroni F, Bianschetti A et al (2002) Expression of functional NR1/NR2B-type NMDA receptors in neuronally differentiated SK–N–SH human cell line. Euro J Neuro Sci 16:2342–2350

    Article  Google Scholar 

  • Rordorf G, Koroshetz WJ, Bonventre JV (1991) Heat shock protects cultured neurons from glutamate toxicity. Neuron 7:1043–1051

    Article  PubMed  CAS  Google Scholar 

  • Schubert D, Piasecki D (2001) Oxidative glutamate toxicity can be a component of the excitotoxicity cascade. J Neuroscience 21:7455–7462

    CAS  Google Scholar 

  • Sharp FR, Massa SM, Swanson RA (1999) Heat shock protein protection. Trends in Neuroscience 22:97–99

    Article  CAS  Google Scholar 

  • Sherman MY, Goldberg AL (2001) Cellular defenses against unfolded proteins: A cell biologist thinks about neurodegenerative diseases. Neuron 29:15–32

    Article  PubMed  CAS  Google Scholar 

  • Tytell M, Greenberg SG, Lasek RJ (1996) Heat shock-like protein is transferred from glia to axon. Brain Res 363:161–164

    Article  Google Scholar 

  • Varju P, Schlett K, Eisel U, Madarász E (2001) Schedule of NMDA receptor subunit expression and functional channel formation in the course of in vitro-induced neurogeneisis. J Neurochem 77:1444–1456

    Article  PubMed  CAS  Google Scholar 

  • Voellmy R (1994) Transduction of the stress signal and mechanisms of transcriptional regulation of heat shock/stress protein gene expression in higher eukaryotes. Critical Rev Eukaryot Gene Expr 4:357–401

    CAS  Google Scholar 

  • Waxman EA, Lynch DR (2005) N-methyl-d-aspartate receptor subtypes: multiple roles in excitotoxicity and neurological disease. Neuroscientist 11:37–49

    Article  PubMed  CAS  Google Scholar 

  • Welch WJ, Gambetti P (1998) Chaperoning brain diseases. Nature 392:23

    Article  PubMed  CAS  Google Scholar 

  • Westerheide SD, Morimoto RI (2005) Heat shock response modulators as therapeutic tools for diseases of protein conformation. J Biol Chem 280:33097–33100

    Article  PubMed  CAS  Google Scholar 

  • Yanagida Y, Mizuno A, Motegi T, Kobatake E, Aizawa M (2000) Electrically stimulated induction of hsp 70 gene expression in mouse astroglia and fibroblast cells. J Biotechnology 79:53–61

    Article  CAS  Google Scholar 

  • Yenari MA, Fink SL, Sun GH et al (1998) Gene therapy with HSP72 is neuroprotective in rat models of stroke and epilepsy. Ann Neurol 44(4):584–591

    Article  PubMed  CAS  Google Scholar 

  • Yenari MA, Giffard RG, Sapolsky RM, Steinberg GK (1999) The neuroprotective potential of heat shock protein 70 (Hsp70). Mol Med Today 5(12):525–531

    Article  PubMed  CAS  Google Scholar 

  • Young JC, Barral JM, Hartl FU (2003) More than folding: localized function of cytosolic chaperones. Trends Biochem Sci 28:541–547

    Article  PubMed  CAS  Google Scholar 

  • Zinsmaier KE, Bronk P (2001) Molecular chaperones and the regulation of neurotransmitter exocytosis. Biochem Pharmacol 2001(62):1–11

    Article  Google Scholar 

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Acknowledgement

We are grateful to Dr. Mark Plummer of the Department of Cell Biology and Neuroscience for providing us with the rat embryonic hippocampal neuron culture (Magby et al. 2006). We thank Dr. Gutian Xiao for the Hsp70 knockout MEF. This work was supported in part by grants from the NSF (MCB0240009) and NJ Commission on Spinal Cord Research (05-3037-SCR-E-0).

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Authors and Affiliations

  1. Department of Cell Biology and Neuroscience, Division of Life Sciences, Rutgers State University of New Jersey, 604 Allison Road, Piscataway, NJ, 08854-8082, USA

    Jay Oza, Jingxian Yang & Alice Y.-C. Liu

  2. Department of Chemistry and Chemical Biology, Rutgers State University of New Jersey, Piscataway, NJ, USA

    Kuang Yu Chen

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  1. Jay Oza
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Correspondence to Alice Y.-C. Liu.

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Oza, J., Yang, J., Chen, K.Y. et al. Changes in the regulation of heat shock gene expression in neuronal cell differentiation. Cell Stress and Chaperones 13, 73–84 (2008). https://doi.org/10.1007/s12192-008-0013-9

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  • DOI: https://doi.org/10.1007/s12192-008-0013-9

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