Cellular and Molecular Life Sciences

, Volume 70, Issue 16, pp 2835–2848 | Cite as

Characterization of tumor differentiation factor (TDF) and its receptor (TDF-R)

  • Izabela Sokolowska
  • Alisa G. Woods
  • Mary Ann Gawinowicz
  • Urmi Roy
  • Costel C. DarieEmail author


Tumor differentiation factor (TDF) is an under-investigated protein produced by the pituitary with no definitive function. TDF is secreted into the bloodstream and targets the breast and prostate, suggesting that it has an endocrine function. Initially, TDF was indirectly discovered based on the differentiation effect of alkaline pituitary extracts of the mammosomatotropic tumor MtTWlO on MTW9/PI rat mammary tumor cells. Years later, the cDNA clone responsible for this differentiation activity was isolated from a human pituitary cDNA library using expression cloning. The cDNA encoded a 108-amino-acid polypeptide that had differentiation activity on MCF7 breast cancer cells and on DU145 prostate cancer cells in vitro and in vivo. Recently, our group focused on identification of the TDF receptor (TDF-R). As potential TDF-R candidates, we identified the members of the Heat Shock 70-kDa family of proteins (HSP70) in both MCF7 and BT-549 human breast cancer cells (HBCC) and PC3, DU145, and LNCaP human prostate cancer cells (HPCC), but not in HeLa cells, NG108 neuroblastoma, or HDF-a and BLK CL.4 cells fibroblasts or fibroblast-like cells. Here we review the current advances on TDF, with particular focus on the structural investigation of its receptor and on its functional effects on breast and prostate cells.


Tumor differentiation factor Receptor Differentiation Mass spectrometry 



Tumor differentiation factor




Human breast cancer cells


Human prostate cancer cells

MCF7 cells

Steroid-responsive breast cancer cells

BT-549 cells

Steroid-resistant breast cancer cells

DU145 cells

Steroid-resistant prostate cancer cells

PC3 cells

Steroid-resistant prostate cancer cells


Steroid-responsive prostate cancer cells


Cervical cancer cells

NG108 cells

Mouse neuroblastoma x rat glioma cells

BLK CL.4 cells

Embryonic fibroblasts-like cells


Human dermal fibroblasts


Open reading frame


Sodium dodecyl sulfate–polyacrylamide gel electrophoresis




Affinity chromatography


Immunoaffinity purification


Mass spectrometry


Electrospray ionization mass spectrometry


Liquid chromatography tandem mass spectrometry


Total ion current




Collision-induced dissociation


Western blotting



GRP78 precursor/BiP

Glucose regulated protein (accession # gi6470150/gi386758)


Heat shock 70-kDa protein 8 isoform 1 (accession # gi62897129/gi5729877)


Heat shock 70-kDa protein (accession # gi386785)


Heat shock 70-kDa protein 1 (accession # gi4529893)


Heat shock 90Bb protein (accession # gi20149594)


Heat shock protein 90 (accession # gi306891)


Heat shock 70-kDa protein 9 (accession # gi12653415)



We would like to thank Dr. Linda Hendershot (St. Jude Children’s Research Hospital, Memphis, TN) for providing the GRP78 clone and for anti-GRP78 antibodies. We would also like to thank Ms. Laura Mulderig and her colleagues (Waters Corporation) for their generous support in setting up the Proteomics Center at Clarkson University. CCD thanks Drs. Thomas A. Neubert (New York University), Belinda Willard (Cleveland Clinic), and Gregory Wolber and David Mclaughin (Eastman Kodak Company) for donation of a TofSpec2E MALDI-MS (each). The authors also thank Jill Pflugheber (St. Lawrence University, Canton, NY) for her advice and support with confocal microscopy and Drs. Mircea Ivan (IUPUI) and Erasmus Schneider (Wadsworth Center) for providing various cell lines. This work was supported in part by Clarkson University (start-up grant to CCD), the Keep a Breast Foundation (KEABF-375-35054), private donations (Ms. Mary Stewart Joyce) and by the U.S. Army research office through the Defense University Research Instrumentation Program (DURIP grant #W911NF-11-1-0304).


  1. 1.
    Platica M, Chen HZ, Ciurea D, Gil J, Mandeli J, Hollander VP (1992) Pituitary extract causes aggregation and differentiation of rat mammary tumor MTW9/Pl cells. Endocrinology 131(6):2573–2580PubMedCrossRefGoogle Scholar
  2. 2.
    Platica M, Ivan E, Holland JF, Ionescu A, Chen S, Mandeli J, Unger PD, Platica O (2004) A pituitary gene encodes a protein that produces differentiation of breast and prostate cancer cells. Proc Natl Acad Sci USA 101(6):1560–1565PubMedCrossRefGoogle Scholar
  3. 3.
    Brabant G, Hoang-Vu C, Cetin Y, Dralle H, Scheumann G, Molne J, Hansson G, Jansson S, Ericson LE, Nilsson M (1993) E-cadherin: a differentiation marker in thyroid malignancies. Cancer Res 53(20):4987–4993PubMedGoogle Scholar
  4. 4.
    De Leeuw WJ, Berx G, Vos CB, Peterse JL, Van de Vijver MJ, Litvinov S, Van Roy F, Cornelisse CJ, Cleton-Jansen AM (1997) Simultaneous loss of E-cadherin and catenins in invasive lobular breast cancer and lobular carcinoma in situ. J Pathol 183(4):404–411PubMedCrossRefGoogle Scholar
  5. 5.
    Edelman GM, Crossin KL (1991) Cell adhesion molecules: implications for a molecular histology. Annu Rev Biochem 60:155–190PubMedCrossRefGoogle Scholar
  6. 6.
    Frixen UH, Behrens J, Sachs M, Eberle G, Voss B, Warda A, Lochner D, Birchmeier W (1991) E-cadherin-mediated cell–cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol 113(1):173–185PubMedCrossRefGoogle Scholar
  7. 7.
    Ray DB, Horst IA, Jansen RW, Kowal J (1981) Normal mammary cells in long-term culture. I. development of hormone-dependent functional monolayer cultures and assay of alpha-lactalbumin production. Endocrinology 108(2):573–583PubMedCrossRefGoogle Scholar
  8. 8.
    Sommers CL, Thompson EW, Torri JA, Kemler R, Gelmann EP, Byers SW (1991) Cell adhesion molecule uvomorulin expression in human breast cancer cell lines: relationship to morphology and invasive capacities. Cell Growth Differ 2(8):365–372PubMedGoogle Scholar
  9. 9.
    Thean ET, Toh BH (1990) Serum human alpha-lactalbumin as a marker for breast cancer. Br J Cancer 61(5):773–775PubMedCrossRefGoogle Scholar
  10. 10.
    Vleminckx K, Vakaet L Jr, Mareel M, Fiers W, van Roy F (1991) Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 66(1):107–119PubMedCrossRefGoogle Scholar
  11. 11.
    Karlin S, Bucher P, Brendel V, Altschul SF (1991) Statistical methods and insights for protein and DNA sequences. Annu Rev Biophys Biophys Chem 20:175–203PubMedCrossRefGoogle Scholar
  12. 12.
    Wootton JC, Federhen S (1996) Analysis of compositionally biased regions in sequence databases. Methods Enzymol 266:554–571PubMedCrossRefGoogle Scholar
  13. 13.
    Bendtsen JD, Jensen LJ, Blom N, Von Heijne G, Brunak S (2004) Feature-based prediction of non-classical and leaderless protein secretion. Protein Eng Des Sel 17(4):349–356PubMedCrossRefGoogle Scholar
  14. 14.
    Roy U, Sokolowska I, Woods AG, Darie CC (2012) Structural investigation of tumor differentiation factor (TDF). Biotechnol Appl Biochem 0 (0):xxx. In PressGoogle Scholar
  15. 15.
    Sokolowska I, Woods AG, Gawinowicz MA, Roy U, Darie CC (2012) Identification of a potential tumor differentiation factor receptor candidate in prostate cancer cells. FEBS J 279(14):2579–2594. doi: 10.1111/j.1742-4658.2012.08641.x PubMedCrossRefGoogle Scholar
  16. 16.
    Sokolowska I, Woods AG, Gawinowicz MA, Roy U, Darie CC (2012) Identification of potential tumor differentiation factor (TDF) receptor from steroid-responsive and steroid-resistant breast cancer cells. J Biol Chem 287(3):1719–1733. doi: 10.1074/jbc.M111.284091 PubMedCrossRefGoogle Scholar
  17. 17.
    Darie CC, Shetty V, Spellman DS, Zhang G, Xu C, Cardasis HL, Blais S, Fenyo D, Neubert TA (2008) Blue Native PAGE and mass spectrometry analysis of the ephrin stimulation-dependent protein–protein interactions in NG108-EphB2 cells. Applications of Mass Spectrometry in life safety, NATO Science for Peace and Security Series. Springer, Berlin Heidelberg New YorkGoogle Scholar
  18. 18.
    Darie CC, Biniossek ML, Gawinowicz MA, Milgrom Y, Thumfart JO, Jovine L, Litscher ES, Wassarman PM (2005) Mass spectrometric evidence that proteolytic processing of rainbow trout egg vitelline envelope proteins takes place on the egg. J Biol Chem 280(45):37585–37598. doi: 10.1074/jbc.M506709200 PubMedCrossRefGoogle Scholar
  19. 19.
    Darie CC, Biniossek ML, Jovine L, Litscher ES, Wassarman PM (2004) Structural characterization of fish egg vitelline envelope proteins by mass spectrometry. Biochemistry 43(23):7459–7478. doi: 10.1021/bi0495937 PubMedCrossRefGoogle Scholar
  20. 20.
    Darie CC, Deinhardt K, Zhang G, Cardasis HS, Chao MV, Neubert TA (2011) Identifying transient protein–protein interactions in EphB2 signaling by blue native PAGE and mass spectrometry. Proteomics 11(23):4514–4528. doi: 10.1002/pmic.201000819 PubMedCrossRefGoogle Scholar
  21. 21.
    Sokolowska I, Dorobantu C, Woods AG, Macovei A, Branza-Nichita N, Darie CC (2012) Proteomic analysis of plasma membranes isolated from undifferentiated and differentiated HepaRG cells. Proteome Sci. 10(1):47. doi: 10.1186/1477-5956-10-47 Google Scholar
  22. 22.
    Sokolowska I, Gawinowicz MA, Ngounou Wetie AG, Darie CC (2012) Disulfide proteomics for identification of extracellular or secreted proteins. Electrophoresis (In Press). doi: 10.1002/elps.201200182
  23. 23.
    Woods AG, Sokolowska I, Darie CC (2012) Identification of consistent alkylation of cysteine-less peptides in a proteomics experiment. Biochem Biophys Res Commun 419(2):305–308. doi: 10.1016/j.bbrc.2012.02.016 PubMedCrossRefGoogle Scholar
  24. 24.
    Woods AG, Sokolowska I, Yakubu R, Butkiewicz M, LaFleur M, Talbot C, Darie CC (2011) Blue Native PAGE and mass spectrometry as an approach for the investigation of stable and transient protein–protein interactions. In: Oxidative stress: diagnostics and therapy. ACS Books. doi: 10.1021/bk-2011-1083.ch012
  25. 25.
    Kelber JA, Panopoulos AD, Shani G, Booker EC, Belmonte JC, Vale WW, Gray PC (2009) Blockade of Cripto binding to cell surface GRP78 inhibits oncogenic Cripto signaling via MAPK/PI3 K and Smad2/3 pathways. Oncogene 28(24):2324–2336PubMedCrossRefGoogle Scholar
  26. 26.
    Ni M, Zhou H, Wey S, Baumeister P, Lee AS (2009) Regulation of PERK signaling and leukemic cell survival by a novel cytosolic isoform of the UPR regulator GRP78/BiP. PLoS ONE 4(8):e6868PubMedCrossRefGoogle Scholar
  27. 27.
    Graner MW, Raynes DA, Bigner DD, Guerriero V (2009) Heat shock protein 70-binding protein 1 is highly expressed in high-grade gliomas, interacts with multiple heat shock protein 70 family members, and specifically binds brain tumor cell surfaces. Cancer Sci 100(10):1870–1879. doi: 10.1111/j.1349-7006.2009.01269.x PubMedCrossRefGoogle Scholar
  28. 28.
    Wu B, Wilmouth RC (2008) Proteomics analysis of immunoprecipitated proteins associated with the oncogenic kinase cot. Mol Cells 25(1):43–49PubMedGoogle Scholar
  29. 29.
    Fu Y, Lee AS (2006) Glucose regulated proteins in cancer progression, drug resistance and immunotherapy. Cancer Biol Ther 5(7):741–744PubMedCrossRefGoogle Scholar
  30. 30.
    Kuwabara H, Yoneda M, Hayasaki H, Nakamura T, Mori H (2006) Glucose-regulated proteins 78 and 75 bind to the receptor for hyaluronan mediated motility in interphase microtubules. Biochem Biophys Res Commun 339(3):971–976PubMedCrossRefGoogle Scholar
  31. 31.
    Lim SO, Park SG, Yoo JH, Park YM, Kim HJ, Jang KT, Cho JW, Yoo BC, Jung GH, Park CK (2005) Expression of heat shock proteins (HSP27, HSP60, HSP70, HSP90, GRP78, GRP94) in hepatitis B virus-related hepatocellular carcinomas and dysplastic nodules. World J Gastroenterol 11(14):2072–2079PubMedGoogle Scholar
  32. 32.
    Fernandez PM, Tabbara SO, Jacobs LK, Manning FC, Tsangaris TN, Schwartz AM, Kennedy KA, Patierno SR (2000) Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions. Breast Cancer Res Treat 59(1):15–26PubMedCrossRefGoogle Scholar
  33. 33.
    Menoret A, Bell G (2000) Purification of multiple heat shock proteins from a single tumor sample. J Immunol Methods 237(1–2):119–130PubMedCrossRefGoogle Scholar
  34. 34.
    Stoeckle MY, Sugano S, Hampe A, Vashistha A, Pellman D, Hanafusa H (1988) 78-kilodalton glucose-regulated protein is induced in Rous sarcoma virus-transformed cells independently of glucose deprivation. Mol Cell Biol 8(7):2675–2680PubMedGoogle Scholar
  35. 35.
    Daneshmand S, Quek ML, Lin E, Lee C, Cote RJ, Hawes D, Cai J, Groshen S, Lieskovsky G, Skinner DG, Lee AS, Pinski J (2007) Glucose-regulated protein GRP78 is up-regulated in prostate cancer and correlates with recurrence and survival. Hum Pathol 38(10):1547–1552PubMedCrossRefGoogle Scholar
  36. 36.
    Didelot C, Lanneau D, Brunet M, Joly AL, De Thonel A, Chiosis G, Garrido C (2007) Anti-cancer therapeutic approaches based on intracellular and extracellular heat shock proteins. Curr Med Chem 14(27):2839–2847PubMedCrossRefGoogle Scholar
  37. 37.
    Solit DB, Rosen N (2006) Hsp90: a novel target for cancer therapy. Curr Top Med Chem 6(11):1205–1214PubMedCrossRefGoogle Scholar
  38. 38.
    Nair SC, Toran EJ, Rimerman RA, Hjermstad S, Smithgall TE, Smith DF (1996) A pathway of multi-chaperone interactions common to diverse regulatory proteins: estrogen receptor, Fes tyrosine kinase, heat shock transcription factor Hsf1, and the aryl hydrocarbon receptor. Cell Stress Chaperones 1(4):237–250PubMedCrossRefGoogle Scholar
  39. 39.
    Nemoto T, Ohara-Nemoto Y, Ota M (1992) Association of the 90-kDa heat shock protein does not affect the ligand-binding ability of androgen receptor. J Steroid Biochem Mol Biol 42(8):803–812PubMedCrossRefGoogle Scholar
  40. 40.
    Sanchez ER, Faber LE, Henzel WJ, Pratt WB (1990) The 56–59-kilodalton protein identified in untransformed steroid receptor complexes is a unique protein that exists in cytosol in a complex with both the 70- and 90-kilodalton heat shock proteins. Biochemistry 29(21):5145–5152PubMedCrossRefGoogle Scholar
  41. 41.
    Veldscholte J, Berrevoets CA, Brinkmann AO, Grootegoed JA, Mulder E (1992) Anti-androgens and the mutated androgen receptor of LNCaP cells: differential effects on binding affinity, heat-shock protein interaction, and transcription activation. Biochemistry 31(8):2393–2399PubMedCrossRefGoogle Scholar
  42. 42.
    Veldscholte J, Berrevoets CA, Zegers ND, van der Kwast TH, Grootegoed JA, Mulder E (1992) Hormone-induced dissociation of the androgen receptor-heat-shock protein complex: use of a new monoclonal antibody to distinguish transformed from nontransformed receptors. Biochemistry 31(32):7422–7430PubMedCrossRefGoogle Scholar
  43. 43.
    Jensen MR, Schoepfer J, Radimerski T, Massey A, Guy CT, Brueggen J, Quadt C, Buckler A, Cozens R, Drysdale MJ, Garcia-Echeverria C, Chene P (2008) NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models. Breast Cancer Res 10(2):R33PubMedCrossRefGoogle Scholar
  44. 44.
    Lanneau D, de Thonel A, Maurel S, Didelot C, Garrido C (2007) Apoptosis versus cell differentiation: role of heat shock proteins HSP90, HSP70 and HSP27. Prion 1(1):53–60PubMedCrossRefGoogle Scholar
  45. 45.
    Seibenhener ML, Babu JR, Geetha T, Wong HC, Krishna NR, Wooten MW (2004) Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol Cell Biol 24(18):8055–8068PubMedCrossRefGoogle Scholar
  46. 46.
    Moscat J, Diaz-Meco MT (2000) The atypical protein kinase Cs. Functional specificity mediated by specific protein adapters. EMBO Rep 1(5):399–403PubMedCrossRefGoogle Scholar
  47. 47.
    Diaz-Meco MT, Moscat J (2001) MEK5, a new target of the atypical protein kinase C isoforms in mitogenic signaling. Mol Cell Biol 21(4):1218–1227PubMedCrossRefGoogle Scholar
  48. 48.
    DeLaBarre B, Brunger AT (2003) Complete structure of p97/valosin-containing protein reveals communication between nucleotide domains. Nat Struct Biol 10(10):856–863PubMedCrossRefGoogle Scholar
  49. 49.
    Vladusic EA, Hornby AE, Guerra-Vladusic FK, Lakins J, Lupu R (2000) Expression and regulation of estrogen receptor beta in human breast tumors and cell lines. Oncol Rep 7(1):157–167PubMedGoogle Scholar
  50. 50.
    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(21):8471–8476. doi: 10.1073/pnas.0903503106 PubMedCrossRefGoogle Scholar
  51. 51.
    Arnold K, Bordoli L, Kopp J, Schwede T (2006) The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 22(2):195–201. doi: 10.1093/bioinformatics/bti770 PubMedCrossRefGoogle Scholar
  52. 52.
    Guex N, Peitsch MC (1997) SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18(15):2714–2723. doi: 10.1002/elps.1150181505 PubMedCrossRefGoogle Scholar
  53. 53.
    Schwede T, Kopp J, Guex N, Peitsch MC (2003) SWISS-MODEL: an automated protein homology-modeling server. Nucleic Acids Res 31(13):3381–3385PubMedCrossRefGoogle Scholar
  54. 54.
    Maiti R, Van Domselaar GH, Zhang H, Wishart DS (2004) SuperPose: a simple server for sophisticated structural superposition. Nucleic Acids Res 32 (Web Server issue):W590-594. doi: 10.1093/nar/gkh477
  55. 55.
    Tovchigrechko A, Vakser IA (2005) Development and testing of an automated approach to protein docking. Proteins 60(2):296–301. doi: 10.1002/prot.20573 PubMedCrossRefGoogle Scholar
  56. 56.
    Tovchigrechko A, Vakser IA (2006) GRAMM-X public web server for protein–protein docking. Nucleic Acids Res 34 (Web Server issue):W310–W314. doi: 10.1093/nar/gkl206
  57. 57.
    Andrusier N, Nussinov R, Wolfson HJ (2007) FireDock: fast interaction refinement in molecular docking. Proteins 69(1):139–159. doi: 10.1002/prot.21495 PubMedCrossRefGoogle Scholar
  58. 58.
    Duhovny D, Nussinov R, Wolfson HJ (2002) Efficient unbound docking of rigid molecules. In: Gussfield et al. (ed) Proceedings of the 2nd Workshop on Algorithms in Bioinformatics (WABI) Lecture Notes in Computer Science Rome, Italy, vol 2452. Springer, pp 185–200Google Scholar
  59. 59.
    Mashiach E, Schneidman-Duhovny D, Andrusier N, Nussinov R, Wolfson HJ (2008) FireDock: a web server for fast interaction refinement in molecular docking. Nucleic Acids Res 36 (Web Server issue):W229–W232. doi: 10.1093/nar/gkn186
  60. 60.
    Schneidman-Duhovny D, Inbar Y, Nussinov R, Wolfson HJ (2005) PatchDock and SymmDock: servers for rigid and symmetric docking. Nucleic Acids Res 33 (Web Server issue):W363–W367. doi: 10.1093/nar/gki481
  61. 61.
    Accelrys_Software Inc (2012) Discovery studio modeling environment, Release 3.1. San Diego. Accelrys Software Inc 1:1–5Google Scholar
  62. 62.
    Ashkenas J, Muschler J, Bissell MJ (1996) The extracellular matrix in epithelial biology: shared molecules and common themes in distant phyla. Dev Biol 180(2):433–444PubMedCrossRefGoogle Scholar
  63. 63.
    Fagotto F, Gumbiner BM (1996) Cell contact-dependent signaling. Dev Biol 180(2):445–454PubMedCrossRefGoogle Scholar
  64. 64.
    Koornstra JJ, de Jong S, Hollema H, de Vries EG, Kleibeuker JH (2003) Changes in apoptosis during the development of colorectal cancer: a systematic review of the literature. Crit Rev Oncol Hematol 45(1):37–53PubMedCrossRefGoogle Scholar
  65. 65.
    Pusztai L, Lewis CE, Lorenzen J, McGee JO (1993) Growth factors: regulation of normal and neoplastic growth. J Pathol 169(2):191–201PubMedCrossRefGoogle Scholar
  66. 66.
    Chen GG, Zeng Q, Tse GM (2008) Estrogen and its receptors in cancer. Med Res Rev 28(6):954–974PubMedCrossRefGoogle Scholar
  67. 67.
    Enmark E, Gustafsson JA (1999) Oestrogen receptors—an overview. J Intern Med 246(2):133–138PubMedCrossRefGoogle Scholar
  68. 68.
    Gustafsson JA (1999) Estrogen receptor beta—a new dimension in estrogen mechanism of action. J Endocrinol 163(3):379–383PubMedCrossRefGoogle Scholar
  69. 69.
    Nilsson S, Makela S, Treuter E, Tujague M, Thomsen J, Andersson G, Enmark E, Pettersson K, Warner M, Gustafsson JA (2001) Mechanisms of estrogen action. Physiol Rev 81(4):1535–1565PubMedGoogle Scholar
  70. 70.
    Zeng Q, Chen G, Vlantis A, Tse G, van Hasselt C (2008) The contributions of oestrogen receptor isoforms to the development of papillary and anaplastic thyroid carcinomas. J Pathol 214(4):425–433PubMedCrossRefGoogle Scholar
  71. 71.
    Kobayashi T, Shimizu Y, Terada N, Yamasaki T, Nakamura E, Toda Y, Nishiyama H, Kamoto T, Ogawa O, Inoue T (2010) Regulation of androgen receptor transactivity and mTOR-S6 kinase pathway by Rheb in prostate cancer cell proliferation. Prostate 70(8):866–874. doi: 10.1002/pros.21120 PubMedGoogle Scholar
  72. 72.
    Yuan X, Balk SP (2009) Mechanisms mediating androgen receptor reactivation after castration. Urol Oncol 27(1):36–41. doi: 10.1016/j.urolonc.2008.03.021 PubMedCrossRefGoogle Scholar
  73. 73.
    Urbanucci A, Waltering KK, Suikki HE, Helenius MA, Visakorpi T (2008) Androgen regulation of the androgen receptor coregulators. BMC Cancer 8:219. doi: 10.1186/1471-2407-8-219 PubMedCrossRefGoogle Scholar
  74. 74.
    Zhu ML, Kyprianou N (2008) Androgen receptor and growth factor signaling cross-talk in prostate cancer cells. Endocr Relat Cancer 15(4):841–849. doi: 10.1677/ERC-08-0084 PubMedCrossRefGoogle Scholar
  75. 75.
    Rinnab L, Hessenauer A, Schutz SV, Schmid E, Kufer R, Finter F, Hautmann RE, Spindler KD, Cronauer MV (2008) Role of androgen receptors in hormone-refractory prostate cancer: molecular basics and experimental therapy approaches. Urologe A 47(3):314–325. doi: 10.1007/s00120-008-1637-1 PubMedCrossRefGoogle Scholar
  76. 76.
    Shimada K, Nakamura M, Ishida E, Higuchi T, Yamamoto H, Tsujikawa K, Konishi N (2008) Prostate cancer antigen-1 contributes to cell survival and invasion though discoidin receptor 1 in human prostate cancer. Cancer Sci 99(1):39–45. doi: 10.1111/j.1349-7006.2007.00655.x PubMedGoogle Scholar
  77. 77.
    Tararova ND, Narizhneva N, Krivokrisenko V, Gudkov AV, Gurova KV (2007) Prostate cancer cells tolerate a narrow range of androgen receptor expression and activity. Prostate 67(16):1801–1815. doi: 10.1002/pros.20662 PubMedCrossRefGoogle Scholar
  78. 78.
    Margiotti K, Wafa LA, Cheng H, Novelli G, Nelson CC, Rennie PS (2007) Androgen-regulated genes differentially modulated by the androgen receptor coactivator l-dopa decarboxylase in human prostate cancer cells. Mol Cancer 6:38. doi: 10.1186/1476-4598-6-38 PubMedCrossRefGoogle Scholar
  79. 79.
    Richter E, Srivastava S, Dobi A (2007) Androgen receptor and prostate cancer. Prostate Cancer Prostatic Dis 10(2):114–118. doi: 10.1038/sj.pcan.4500936 PubMedCrossRefGoogle Scholar
  80. 80.
    Reddy GP, Barrack ER, Dou QP, Menon M, Pelley R, Sarkar FH, Sheng S (2006) Regulatory processes affecting androgen receptor expression, stability, and function: potential targets to treat hormone-refractory prostate cancer. J Cell Biochem 98(6):1408–1423. doi: 10.1002/jcb.20927 PubMedCrossRefGoogle Scholar
  81. 81.
    Dehm SM, Tindall DJ (2006) Molecular regulation of androgen action in prostate cancer. J Cell Biochem 99(2):333–344. doi: 10.1002/jcb.20794 PubMedCrossRefGoogle Scholar
  82. 82.
    Hobisch A, Fritzer A, Comuzzi B, Fiechtl M, Malinowska K, Steiner H, Bartsch G, Culig Z (2006) The androgen receptor pathway is by-passed in prostate cancer cells generated after prolonged treatment with bicalutamide. Prostate 66(4):413–420. doi: 10.1002/pros.20365 PubMedCrossRefGoogle Scholar
  83. 83.
    Dong Y, Zhang H, Gao AC, Marshall JR, Ip C (2005) Androgen receptor signaling intensity is a key factor in determining the sensitivity of prostate cancer cells to selenium inhibition of growth and cancer-specific biomarkers. Mol Cancer Ther 4(7):1047–1055. doi: 10.1158/1535-7163.MCT-05-0124 PubMedCrossRefGoogle Scholar
  84. 84.
    Linja MJ, Visakorpi T (2004) Alterations of androgen receptor in prostate cancer. J Steroid Biochem Mol Biol 92(4):255–264PubMedCrossRefGoogle Scholar
  85. 85.
    Marandola P, Bonghi A, Jallous H, Bombardelli E, Morazzoni P, Gerardini M, Tiscione D, Albergati F (2004) Molecular biology and the staging of prostate cancer. Ann N Y Acad Sci 1028:294–312. doi: 1028/1/29410.1196/annals.1322.034 PubMedCrossRefGoogle Scholar
  86. 86.
    Sommer A, Haendler B (2003) Androgen receptor and prostate cancer: molecular aspects and gene expression profiling. Curr Opin Drug Discov Dev 6(5):702–711Google Scholar
  87. 87.
    Suzuki H, Ueda T, Ichikawa T, Ito H (2003) Androgen receptor involvement in the progression of prostate cancer. Endocr Relat Cancer 10(2):209–216PubMedCrossRefGoogle Scholar
  88. 88.
    Gioeli D, Ficarro SB, Kwiek JJ, Aaronson D, Hancock M, Catling AD, White FM, Christian RE, Settlage RE, Shabanowitz J, Hunt DF, Weber MJ (2002) Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites. J Biol Chem 277(32):29304–29314. doi: 10.1074/jbc.M204131200 PubMedCrossRefGoogle Scholar
  89. 89.
    Haendler B (2002) Androgen-selective gene regulation in the prostate. Biomed Pharmacother 56(2):78–83PubMedCrossRefGoogle Scholar
  90. 90.
    Sadar MD, Hussain M, Bruchovsky N (1999) Prostate cancer: molecular biology of early progression to androgen independence. Endocr Relat Cancer 6(4):487–502PubMedCrossRefGoogle Scholar
  91. 91.
    Griffiths K, Morton MS, Nicholson RI (1997) Androgens, androgen receptors, antiandrogens and the treatment of prostate cancer. Eur Urol 32(Suppl 3):24–40PubMedGoogle Scholar
  92. 92.
    Corona G, Baldi E, Maggi M (2011) Androgen regulation of prostate cancer: where are we now? J Endocrinol Invest 34(3):232–243PubMedGoogle Scholar
  93. 93.
    Loda M, Kaelin WG Jr (2010) Prostate cancer: beta control your hormones. Cancer Cell 17(4):311–312PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel 2012

Authors and Affiliations

  • Izabela Sokolowska
    • 1
  • Alisa G. Woods
    • 1
  • Mary Ann Gawinowicz
    • 2
  • Urmi Roy
    • 1
  • Costel C. Darie
    • 1
    Email author
  1. 1.Biochemistry and Proteomics Group, Department of Chemistry and Biomolecular ScienceClarkson UniversityPotsdamUSA
  2. 2.Protein Core Facility, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA

Personalised recommendations