Attenuation of androgen receptor-dependent transcription by the serine/threonine kinase Pim-1.
Androgens play a key role in the regulation of the normal prostate as well as in the promotion and progression of prostate cancer. Recently, an oncogenic serine/threonine kinase, Pim-1, was reported to be overexpressed in prostate cancer. To elucidate whether Pim-1 is capable of modulating androgen signaling, we studied the effects of Pim-1 on androgen receptor (AR)-dependent transcription. Under transient transfection conditions, Pim-1 attenuated transcriptional activity of AR in a dose-dependent fashion in PC-3, HeLa, and COS-1 cells, whereas a kinase-negative mutant of Pim-1, Pim-1(K67M), showed no repressive activity. In contrast, ectopic expression of Pim-1 did not influence the activity of endogenous AR in LNCaP cells. This was, however, not a result of the T877A mutation present in AR of LNCaP cells, because that AR mutant was repressed by Pim-1 as efficiently as wild-type AR when expressed in PC-3 prostate cancer cells. Pim-1 inhibited AR mutants devoid of the ligand-binding domain or the core amino-terminal transactivation function but failed to influence the DNA binding of AR. Because we found no evidence for phosphorylation of AR by Pim-1 or for direct interaction between these proteins, Pim-1 is likely to influence AR activity via an indirect mechanism, possibly involving phosphorylation of a coregulator and/or a component of the transcription machinery. Overexpression of Pim-1 may thus attenuate androgen response during progression of prostate cancer in a cell context-dependent fashion.
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D051573:Proto-Oncogene Proteins c-pim-1; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; C496634:PIM1 protein, human; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1