Document Detail


Regulation of a novel androgen receptor target gene, the cyclin B1 gene, through androgen-dependent E2F family member switching.
MedLine Citation:
PMID:  22508987     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The malignant transformation of human prostatic epithelium is associated with the loss of androgen receptor (AR) in the surrounding stroma. However, the function and mechanisms of AR signaling in prostate cancer (PCa) stroma remain elusive. Here we report, by using proteomics pathway array analysis (PPAA), that androgen and its receptor inhibit the proliferation of prostate stromal cells through transcriptional suppression of cyclin B1, and we confirmed our findings at mRNA and protein levels using AR-negative or -positive primary prostate stromal cells. Furthermore, AR showed a negative correlation with cyclin B1 expression in stroma of human PCa samples in vivo. Mechanistically, we identify cyclin B1 as a bona fide AR target gene in prostate stromal cells. The negative regulation of cyclin B1 by AR is mediated through switching between E2F1 and E2F4 on the promoter of cyclin B1. E2F1 binds to the cyclin B1 promoter and maintains its expression and subsequent cell cycle progression in AR-negative stromal cells or AR-positive stromal cells when androgens are depleted. Upon stimulation with androgen in AR-positive stromal cells, E2F1 is displaced from the binding site by AR and replaced with E2F4, leading to the recruitment of the silencing mediator for retinoid and thyroid hormone receptor (SMRT)/histone deacetylase 3 (HDAC3) corepressor complex and repression of cyclin B1 at the chromatin level. The switch between E2F1 and E2F4 at the E2F binding site of the cyclin B1 promoter coincides with an androgen-dependent interaction between AR and E2F1 as well as the cytoplasmic-to-nuclear translocation of E2F4. Thus, we identified a novel mechanism for E2F factors in the regulation of cell cycle gene expression and cell cycle progression under the control of AR signaling.
Authors:
Yirong Li; David Y Zhang; Qinghu Ren; Fei Ye; Xin Zhao; Garrett Daniels; Xinyu Wu; Brian Dynlacht; Peng Lee
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-04-16
Journal Detail:
Title:  Molecular and cellular biology     Volume:  32     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-06-11     Completed Date:  2012-09-06     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2454-66     Citation Subset:  IM    
Affiliation:
Department of Pathology, New York University School of Medicine, New York Harbor Healthcare System, NY, USA.
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MeSH Terms
Descriptor/Qualifier:
Androgens / metabolism*
Cell Cycle Checkpoints / genetics,  physiology
Cell Line
Cell Proliferation
Cyclin B1 / genetics*,  metabolism
E2F Transcription Factors / metabolism*
E2F1 Transcription Factor / metabolism
E2F4 Transcription Factor / metabolism
Gene Expression Regulation
Histone Deacetylases / metabolism
Humans
Male
Models, Biological
Nuclear Receptor Co-Repressor 2 / metabolism
Promoter Regions, Genetic
Prostate / cytology,  metabolism
Protein Binding
Proteomics
RNA, Messenger / genetics,  metabolism
Receptors, Androgen / metabolism*
Signal Transduction
Stromal Cells / cytology,  metabolism
Grant Support
ID/Acronym/Agency:
1U01CA149556-01/CA/NCI NIH HHS; 1UL1RR029893/RR/NCRR NIH HHS; 5R01 CA077245-10/CA/NCI NIH HHS; R01 CA077245/CA/NCI NIH HHS; T32 CA009161/CA/NCI NIH HHS; T32 CA009161/CA/NCI NIH HHS; U01 CA149556/CA/NCI NIH HHS; UL1 RR029893/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/AR protein, human; 0/Androgens; 0/Cyclin B1; 0/E2F Transcription Factors; 0/E2F1 Transcription Factor; 0/E2F1 protein, human; 0/E2F4 Transcription Factor; 0/E2F4 protein, human; 0/NCOR2 protein, human; 0/Nuclear Receptor Co-Repressor 2; 0/RNA, Messenger; 0/Receptors, Androgen; EC 3.5.1.98/Histone Deacetylases; EC 3.5.1.98/histone deacetylase 3
Comments/Corrections

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