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

@article{Gamble2007ProhibitinAP,
  title={Prohibitin, a protein downregulated by androgens, represses androgen receptor activity},
  author={Simon C. Gamble and D Chotai and Michael Odontiadis and D. Alwyn Dart and Greg N. Brooke and Sue M. Powell and Vikash Reebye and Anabel Varela-Carver and Yoshiaki Kawano and Jonathan Waxman and Charlotte Lynne Bevan},
  journal={Oncogene},
  year={2007},
  volume={26},
  pages={1757-1768}
}
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… 
A repressive role for prohibitin in estrogen signaling.
TLDR
It is demonstrated that prohibitin (PHB), a potential tumor suppressor, functions as a potent transcriptional corepressor for estrogen receptor alpha (ERalpha) in vitro and in vivo and that its heteromerization with REA acts as a novel mechanism to limit its core pressor activity.
The prohibitin-repressive interaction with E2F1 is rapidly inhibited by androgen signalling in prostate cancer cells
TLDR
The AR and androgens may deactivate the repressive functions of PHB upon E2F1 leading to cell cycle progression, and indicates a role for AR in DNA replication licensing.
Reducing prohibitin increases histone acetylation, and promotes androgen independence in prostate tumours by increasing androgen receptor activation by adrenal androgens
TLDR
Reduction in PHB levels is sufficient to lower the threshold of AR activity in vitro and in vivo; this may be via a general increase in histone acetylation that could potentially affect signalling by other transcription factors.
Androgen receptor epigenetics
TLDR
A focus is on AR interactions with chromatin and how they regulate AR function in PCa development and progression and the role of DNA methylation in the epigenetic regulation of gene expression is appreciated.
Prohibitin and the SWI/SNF ATPase subunit BRG1 are required for effective androgen antagonist-mediated transcriptional repression of androgen receptor-regulated genes.
TLDR
It is shown that prohibitin may function through BRG1-mediated local chromatin remodeling activity and the removal of p300-mediated acetylation to produce androgen antagonist-mediated transcriptional repression of prostate cancer cells.
Inability of NCoR/SMRT to repress androgen receptor transcriptional activity in prostate cancer cell lines.
TLDR
Evidence is provided that up-regulation of NCoR or SMRT may increase transcriptional activity of the AR in a cell type-specific context and it is found that N co-R/SMRT overexpression did not repress AR-dependent gene expression in the PCa cell lines, but rather activated it.
Manipulating prohibitin levels provides evidence for an in vivo role in androgen regulation of prostate tumours
TLDR
This study provides proof of principle that reduction in PHB promotes both androgen-dependent and ‘androgen-independent’ tumour growth, and altering AR activity via increasing levels or activity of corepressors is a valid therapeutic strategy for advanced prostate cancer.
Androgen-regulated processing of the oncomir miR-27a, which targets Prohibitin in prostate cancer.
TLDR
It is demonstrated that miR-27a is an androgen-regulated oncomir in prostate cancer, acting via targeting the tumour suppressor and AR corepressor, Prohibitin, and it is shown that a miR -27a anti-sense oligonucleotide, by opposing the effects of mir- 27a, has therapeutic potential in prostatecancer.
Estrogen-regulated prohibitin is required for mouse uterine development and adult function.
TLDR
It is demonstrated that prohibitin (PHB) is an estrogen-regulated gene in vitro and in vivo, and its expression is induced by estrogen in the uterus, suggesting the existence of feedback regulatory loops.
Mechanisms of androgen receptor activation in advanced prostate cancer: differential co-activator recruitment and gene expression
TLDR
The findings suggest that mutant receptors, activated by alternative ligands, drive growth via different mechanisms to androgen-activated wild-type receptor, as distinct subsets of genes may be regulated.
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References

SHOWING 1-10 OF 46 REFERENCES
Bicalutamide Functions as an Androgen Receptor Antagonist by Assembly of a Transcriptionally Inactive Receptor*
TLDR
It is demonstrated that bicalutamide stimulates the assembly of a transcriptionally inactive AR on DNA and support altered coactivator expression as a mechanism of bICALutamide-resistant androgen-independent PCa.
Retinoblastoma, a tumor suppressor, is a coactivator for the androgen receptor in human prostate cancer DU145 cells.
TLDR
The discovery that Rb can function as a coactivator to induce AR transcriptional activity in prostate cells may represent the first data to link a negative growth regulatory protein function in a positive manner, by inducing the transcriptionalactivity of AR.
Inhibition of the dihydrotestosterone-activated androgen receptor by nuclear receptor corepressor.
TLDR
It is demonstrated that NCoR interacts directly with the androgen receptor (AR) and represses dihydrotestosterone-stimulated AR transcriptional activity and the possibility of developing selective AR modulators that enhance this interaction is suggested.
Prohibitin, a potential tumor suppressor, interacts with RB and regulates E2F function
TLDR
It is believed that prohibitin is a novel regulator of E2F activity that responds to specific signaling cascades, and physically interacts with all three Rb family proteins in vitro and in vivo.
Prohibitin Induces the Transcriptional Activity of p53 and Is Exported from the Nucleus upon Apoptotic Signaling*
TLDR
It is shown that prohibitin is predominantly nuclear in two breast cancer cell lines where it co-localizes with E2F1 and p53 and is capable of modulating Rb/E2F as well as p53 regulatory pathways.
Human Checkpoint Protein hRad9 Functions as a Negative Coregulator To Repress Androgen Receptor Transactivation in Prostate Cancer Cells
TLDR
The identification of hRad9, a key member of the checkpoint Rad protein family, as a coregulator to suppress androgen-AR transactivation in prostate cancer cells is reported, providing the first linkage between androgen -AR signals and radiation-induced responses.
Androgens target prohibitin to regulate proliferation of prostate cancer cells
TLDR
It seems that the regulation of prohibitin is a vital part of the cellular growth response to androgen stimulation in LNCaPs and prohibitin may have a nuclear regulatory role in cell-cycle progression.
Differential regulation of Rb family proteins and prohibitin during camptothecin-induced apoptosis
TLDR
It is found that prohibitin protects cells from apoptosis mediated by camptothecin, a topoisomerase I inhibitor, and may be inhibiting apoptosis by downregulating E2F activity when Rb family members are inactive.
Prohibitin co-localizes with Rb in the nucleus and recruits N-CoR and HDAC1 for transcriptional repression
TLDR
Prohibitin appears to repress E2F-mediated transcription utilizing different molecular mediators and facilitate channeling of specific signaling pathways to the cell cycle machinery.
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