p53 represses androgen-induced transactivation of prostate-specific antigen by disrupting hAR amino- to carboxyl-terminal interaction.
Prostate-specific antigen (PSA) is highly overexpressed in prostate cancer. One important regulator of PSA expression is the androgen receptor (AR), the nuclear receptor that mediates the biological actions of androgens. AR is able to up-regulate PSA expression by directly binding and activating the promoter of this gene. We provide evidence here that that this AR activity is repressed by the tumor suppressor protein p53. p53 appears to exert its inhibition of human AR (hAR) by disrupting its amino- to carboxyl-terminal (N-to-C) interaction, which is thought to be responsible for the homodimerization of this receptor. Consistent with this, p53 is also able to block hAR DNA binding in vitro. Our previous data have shown that c-Jun can mediate hAR transactivation, and this appears to result from a positive effect on hAR N-to-C interaction and DNA binding. Interestingly, c-Jun is able to relieve the negative effects of p53 on hAR transactivation, N-to-C interaction, and DNA binding, demonstrating antagonistic activities of these two proteins. Importantly, a p53 mutation found in metastatic prostate cancer severely disrupts the p53 negative activity on hAR, suggesting that the inability of p53 mutants to down-regulate hAR is, in part, responsible for the metastatic phenotype.
Shenk
J L
JL
Department of Biological Sciences, University of Toledo, Ohio 43606, USA.
Fisher
C J
CJ
Chen
S Y
SY
Zhou
X F
XF
Tillman
K
K
Shemshedini
L
L
D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism* / Q000502:physiology*; D015854:Up-Regulation
D016755:Proto-Oncogene Proteins c-jun; D011944:Receptors, Androgen; D016159:Tumor Suppressor Protein p53; D004247:DNA; D008156:Luciferases; D015500:Chloramphenicol O-Acetyltransferase; D017430:Prostate-Specific Antigen