Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Prohibitin, a protein downregulated by androgens, represses androgen receptor activity

Oncogene volume 26, pages 1757–1768 (2007)Cite this article

Abstract

Prohibitin (PHB) is a cell cycle regulatory protein, known to repress E2F1-mediated gene activation via recruitment of transcriptional regulatory factors such as retinoblastoma and histone deacetylase 1 (HDAC1). We previously identified PHB as a target protein of androgen signaling in prostate cancer cells and showed that downregulation of PHB is required for androgen-induced cell cycle entry in these cells. We now present evidence that PHB, which has 54% homology at the protein level to the oestrogen receptor corepressor REA (repressor of oestrogen receptor activity), can repress androgen receptor (AR)-mediated transcription and androgen-dependent cell growth. Depletion of endogenous PHB resulted in an increase in expression of the androgen-regulated prostate-specific antigen gene. The repression appears to be specific to androgen and closely related receptors, as it is also evident for the glucocorticoid and progesterone, but not oestrogen, receptors. In spite of interaction of PHB with HDAC1, HDAC activity is not required for this repression. Although AR and PHB could be co-immunoprecipitated, no direct interaction was detectable, suggesting that PHB forms part of a repressive complex with the AR. Competition with the co-activator SRC1 further suggests that formation of a complex with AR, PHB and other cofactors is the mechanism by which repression is achieved. It appears then that repression of AR activity is one mechanism by which PHB inhibits androgen-dependent growth of prostate cells. Further, this study implies that the AR itself could, by mediating downregulation of a corepressor, be involved in the progression of prostate tumours to the hormone refractory stage.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Adegbola O, Pasternack GR . (2005). A pp32-retinoblastoma protein complex modulates androgen receptor-mediated transcription and associates with components of the splicing machinery. Biochem Biophys Res Commun 334: 702–708.

    Article  CAS  Google Scholar 

  • Belandia B, Parker MG . (2003). Nuclear receptors: a rendezvous for chromatin remodeling factors. Cell 114: 277–280.

    Article  CAS  Google Scholar 

  • Berrevoets CA, Umar A, Trapman J, Brinkmann AO . (2004). Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR). Biochem J 379: 731–738.

    Article  CAS  Google Scholar 

  • Bevan CL, Parker MG . (1999). The role of coactivators in steroid hormone action. Exp Cell Res 253: 349–356.

    Article  CAS  Google Scholar 

  • Brinkmann AO, Faber PW, van Rooij HCJ, Kuiper GGJM, Ris C, Klaasen P et al. (1989). The human androgen receptor: domain structure, genomic organisation and regulation of expression. J Steroid Biochem 34: 307–310.

    Article  CAS  Google Scholar 

  • Burd CJ, Petre CE, Moghadam H, Wilson EM, Knudsen KE . (2005). Cyclin D1 binding to the androgen receptor (AR) NH2-terminal domain inhibits activation function 2 association and reveals dual roles for AR corepression. Mol Endocrinol 19: 607–620.

    Article  CAS  Google Scholar 

  • Chen C, Okayama H . (1987). High efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol 7: 2745–2752.

    Article  CAS  Google Scholar 

  • Cheng S, Brzostek S, Lee SR, Hollenberg AN, Balk SP . (2002). Inhibition of the dihydrotestosterone-activated androgen receptor by nuclear receptor corepressor. Mol Endocrinol 16: 1492–1501.

    Article  CAS  Google Scholar 

  • Coates PJ, Jamieson DJ, Smart K, Prescott AR, Hall PA . (1997). The prohibitin family of mitochondrial proteins regulate replicative lifespan. Curr Biol 7: 607–610.

    Article  CAS  Google Scholar 

  • Delage-Mourroux R, Martini PG, Choi I, Kraichely DM, Hoeksema J, Katzenellenbogen BS . (2000). Analysis of estrogen receptor interaction with a repressor of estrogen receptor activity (REA) and the regulation of estrogen receptor transcriptional activity by REA. J Biol Chem 275: 35848–35856.

    Article  CAS  Google Scholar 

  • Dubbink HJ, Hersmus R, Verma CS, van der Korput HA, Berrevoets CA, van Tol J et al. (2004). Distinct recognition modes of FXXLF and LXXLL motifs by the androgen receptor. Mol Endocrinol 18: 2132–2150.

    Article  CAS  Google Scholar 

  • Fusaro G, Dasgupta P, Rastogi S, Joshi B, Chellappan S . (2003). Prohibitin induces the transcriptional activity of p53 and is exported from the nucleus upon apoptotic signaling. J Biol Chem 278: 47853–47861.

    Article  CAS  Google Scholar 

  • Fusaro G, Wang S, Chellappan S . (2002). Differential regulation of Rb family proteins and prohibitin during camptothecin-induced apoptosis. Oncogene 21: 4539–4548.

    Article  CAS  Google Scholar 

  • Gamble SC, Odontiadis M, Waxman J, Westbrook JA, Dunn MJ, Wait R et al. (2004). Androgens target prohibitin to regulate proliferation of prostate cancer cells. Oncogene 23: 2996–3004.

    Article  CAS  Google Scholar 

  • Ho YS, Crapo JD . (1988). Isolation and characterization of complementary DNAs encoding human manganese-containing superoxide dismutase. FEBS Lett 229: 256–260.

    Article  CAS  Google Scholar 

  • Hu X, Lazar MA . (2000). Transcriptional repression by nuclear hormone receptors. Trends Endocrinol Metab 11: 6–10.

    Article  CAS  Google Scholar 

  • Hur E, Pfaff SJ, Payne ES, Gron H, Buehrer BM, Fletterick RJ . (2004). Recognition and accommodation at the androgen receptor coactivator binding interface. PLoS Biol 2: E274.

    Article  Google Scholar 

  • Jackson TA, Richer JK, Bain DL, Takimoto GS, Tung L, Horwitz KB . (1997). The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-Cor or SMRT. Mol Endocrinol 11: 693–705.

    Article  CAS  Google Scholar 

  • Joshi B, Ko D, Ordonez-Ercan D, Chellappan SP . (2003). A putative coiled-coil domain of prohibitin is sufficient to repress E2F1-mediated transcription and induce apoptosis. Biochem Biophys Res Commun 312: 459–466.

    Article  CAS  Google Scholar 

  • Kalkhoven E, Kwakkenbos-Isbrucker L, de Laat SW, van der Saag PT, van der Burg B . (1994). Synthetic progestins induce proliferation of breast tumor cell lines via the progesterone or estrogen receptor. Mol Cell Endocrinol 102: 45–52.

    Article  CAS  Google Scholar 

  • Kalkhoven E, Valentine JE, Heery DM, Parker MG . (1998). Isoforms of steroid receptor co-activator 1 differ in their ability to potentiate transcription by the oestrogen receptor. EMBO J 17: 232–243.

    Article  CAS  Google Scholar 

  • Lavinsky RM, Jepsen K, Heinzel T, Torchia J, Mullen T-M, Schiff R et al. (1998). Diverse signalling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. Proc Natl Acad Sci USA 95: 2920–2925.

    Article  CAS  Google Scholar 

  • Masiello D, Cheng S, Bubley GJ, Lu ML, Balk SP . (2002). Bicalutamide functions as an androgen receptor antagonist by assembly of a transcriptionally inactive receptor. J Biol Chem 277: 26321–26326.

    Article  CAS  Google Scholar 

  • McClung JK, Danner DB, Stewart DA, Smith JR, Schneider EL, Lumpkin CK et al. (1989). Isolation of a cDNA that hybrid selects antiproliferative mRNA from rat liver. Biochem Biophys Res Commun 164: 1316–1322.

    Article  CAS  Google Scholar 

  • Metivier R, Penot G, Hubner MR, Reid G, Brand H, Kos M et al. (2003). Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell 115: 751–763.

    Article  CAS  Google Scholar 

  • Montano MM, Ekena K, Delage-Mourroux R, Chang W, Martini P, Katzenellenbogen B . (1999). An estrogen receptor-selective coregulator that potentiates the effectiveness of antiestrogens and represses the activity of estrogens. Proc Natl Acad Sci USA 96: 6947–6952.

    Article  CAS  Google Scholar 

  • Nijtmans LG, de Jong L, Artal Sanz M, Coates PJ, Berden JA, Back JW et al. (2000). Prohibitins act as a membrane-bound chaperone for the stabilization of mitochondrial proteins. EMBO J 19: 2444–2451.

    Article  CAS  Google Scholar 

  • Nuell MJ, Stewart DA, Walker L, Friedman V, Wood CM, Owens GA et al. (1991). Prohibitin, an evolutionarily conserved intracellular protein that blocks DNA synthesis in normal fibroblasts and HeLa cells. Mol Cell Biol 11: 1372–1381.

    Article  CAS  Google Scholar 

  • Rajalingam K, Wunder C, Brinkmann V, Churin Y, Hekman M, Sievers C et al. (2005). Prohibitin is required for Ras-induced Raf-MEK-ERK activation and epithelial cell migration. Nat Cell Biol 7: 837–843.

    Article  CAS  Google Scholar 

  • Shang Y, Myers M, Brown M . (2002). Formation of the androgen receptor transcription complex. Mol Cell 9: 601–610.

    Article  CAS  Google Scholar 

  • Smith CL, Nawaz Z, O'Malley BW . (1997). Coactivator and corepressor regulation agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. Mol Endocrinol 12: 657–666.

    Article  Google Scholar 

  • Steglich G, Neupert W, Langer T . (1999). Prohibitins regulate membrane protein degradation by the m-AAA protease in mitochondria. Mol Cell Biol 19: 3435–3442.

    Article  CAS  Google Scholar 

  • Thompson WE, Branch A, Whittaker JA, Lyn D, Zilberstein M, Mayo KE et al. (2001). Characterization of prohibitin in a newly established rat ovarian granulosa cell line. Endocrinology 142: 4076–4085.

    Article  CAS  Google Scholar 

  • Tora L, Mullick A, Metzger D, Ponglikitmongkol M, Park I, Chambon P . (1989). The cloned human oestrogen receptor contains a mutation which alters its hormone binding properties. EMBO J 8: 1981–1986.

    Article  CAS  Google Scholar 

  • Verrijdt G, Schoenmakers E, Haelens A, Peeters B, Verhoeven G, Rombauts W et al. (2000). Change of specificity mutations in androgen-selective enhancers. Evidence for a role of differential DNA binding by the androgen receptor. J Biol Chem 275: 12298–12305.

    Article  CAS  Google Scholar 

  • Wagner BL, Norris JD, Knotts TA, Weigel NL, McDonnell DP . (1998). The nuclear corepressors NCoR and SMRT are key regulators of both ligand- and 8-bromo-cyclic AMP-dependent transcriptional activity of the human progesterone receptor. Mol Cell Biol 18: 1369–1378.

    Article  CAS  Google Scholar 

  • Wang L, Hsu CL, Ni J, Wang PH, Yeh S, Keng P et al. (2004a). Human checkpoint protein hRad9 functions as a negative coregulator to repress androgen receptor transactivation in prostate cancer cells. Mol Cell Biol 24: 2202–2213.

    Article  CAS  Google Scholar 

  • Wang S, Fusaro G, Padmanabhan J, Chellappan SP . (2002). Prohibitin co-localizes with Rb in the nucleus and recruits N-CoR and HDAC1 for transcriptional repression. Oncogene 21: 8388–8396.

    Article  CAS  Google Scholar 

  • Wang S, Nath N, Adlam M, Chellappan S . (1999). Prohibitin, a potential tumor suppressor, interacts with RB and regulates E2F function. Oncogene 18: 3501–3510.

    Article  CAS  Google Scholar 

  • Wang S, Zhang B, Faller DV . (2004b). BRG1/BRM and prohibitin are required for growth suppression by estrogen antagonists. EMBO J 23: 2293–2303.

    Article  CAS  Google Scholar 

  • Whitaker HC, Hanrahan S, Totty N, Gamble SC, Waxman J, Cato AC et al. (2004). Androgen receptor is targeted to distinct subcellular compartments in response to different therapeutic antiandrogens. Clin Cancer Res 10: 7392–7401.

    Article  CAS  Google Scholar 

  • Yeh S, Miyamoto H, Nishimura K, Kang H, Ludlow J, Hsiao P et al. (1998). Retinoblastoma, a tumor suppressor, is a coactivator for the androgen receptor in human prostate cancer DU145 cells. Biochem Biophys Res Commun 248: 361–367.

    Article  CAS  Google Scholar 

  • Zhang X, Jeyakumar M, Petukhov S, Bagchi M . (1998). A nuclear receptor corepressor modulates transcriptional activity of antagonist-occupied steroid hormone receptor. Mol Endocrinol 12: 513–524.

    Article  CAS  Google Scholar 

  • Zhou Z-X, Lane MV, Kemppainen JA, French FS, Wilson EM . (1995). Specificity of ligand-dependent androgen receptor stabilization: receptor domain interactions influence ligand dissociation and receptor stability. Mol Endocrinol 9: 208–218.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Simak Ali for critical discussion and reading of the paper and Hayley Whitaker for the PHB/REA alignment. We also thank Andrew Cato for the kind gift of PC3wtAR cells and Malcolm Parker, Frank Claessens, Albert Brinkmann, Guido Jenster, Simak Ali, Marc van der Wetering and Hans Clevers for kindly providing plasmids used in this study. This work was funded by grants from the Whyte Family Charitable Trust, The Prostate Cancer Charity and the Association for International Cancer Research.

Author information

Authors and Affiliations

  1. Department of Oncology, Imperial College London, Hammersmith Hospital Campus, London, UK

    S C Gamble, D Chotai, M Odontiadis, D A Dart, G N Brooke, S M Powell, V Reebye, A Varela-Carver, Y Kawano, J Waxman & C L Bevan

Authors
  1. S C Gamble
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Chotai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Odontiadis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D A Dart
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G N Brooke
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S M Powell
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. V Reebye
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Varela-Carver
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Y Kawano
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J Waxman
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. C L Bevan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C L Bevan.

Additional information

Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gamble, S., Chotai, D., Odontiadis, M. et al. Prohibitin, a protein downregulated by androgens, represses androgen receptor activity. Oncogene 26, 1757–1768 (2007). https://doi.org/10.1038/sj.onc.1209967

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209967

Keywords

This article is cited by

Search

Advanced search

Quick links