Retinoblastoma, a tumor suppressor, is a coactivator for the androgen receptor in human prostate cancer DU145 cells.
The retinoblastoma protein may function as a tumor suppressor by controlling the progression of the normal cell cycle. Inactivation of Rb has been regarded as an important event in prostate carcinogenesis. However, the detailed mechanism of how Rb is linked to androgen-androgen receptor (A-AR), the major factor in promotion of prostate tumor growth, remains unclear. Using GST-Rb pull down assay and mammalian two-hybrid system, we report here that Rb can bind specifically to AR in an androgen-independent manner. Transient transfection assay demonstrates that cotransfection of AR and Rb can further induce AR transcriptional activity 4-fold in the presence of 1 nM dihydrotestosterone in DU145 cells. Interestingly, cotransfection of Rb and ARA70, the first identified AR coactivator, with AR can additively induce AR transcriptional activity 13-fold (from 5-fold to 64-fold). In conclusion, our 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 transcriptional activity of AR.
Departments of Pathology, Urology, and Biochemistry, University of Rochester, Rochester, New York, 14642, USA.
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S
Yeh
H
H
Miyamoto
K
K
Nishimura
H
H
Kang
J
J
Ludlow
P
P
Hsiao
C
C
Wang
C
C
Su
C
C
Chang
D002453:Cell Cycle / Q000502:physiology; D013196:Dihydrotestosterone / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008297:Male; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000235:genetics; D014162:Transfection / Q000235:genetics; D014407:Tumor Cells, Cultured
C111382:NCOA4 protein, human; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D015534:Trans-Activators; D014157:Transcription Factors; D013196:Dihydrotestosterone