Rapid signalling by androgen receptor in prostate cancer cells.
Androgens are important growth regulators in prostate cancer. Their known mode of action in target cells requires binding to a cytoplasmic androgen receptor followed by a nuclear translocation event and modulation of the expression of specific genes. Here, we report another mode of action of this receptor. Treatment of androgen responsive prostate cancer cells with dihydrotestosterone leads to a rapid and reversible activation of mitogen-activated protein kinases MAPKs (also called extracellular signal-regulated kinases or Erks). Transient transfection assays demonstrated that the androgen receptor-mediated activation of MAP kinase results in enhanced activity of the transcription factor Elk-1. This action of the androgen receptor differs from its known transcriptional activity since it is rapid and insensitive to androgen antagonists such as hydroxyflutamide or casodex. Biochemical studies as well as analyses with dominant negative mutants showed the involvement of kinases such as MAPK/Erk kinase, phosphatidyl-inositol 3-kinase and protein kinase C in the androgen receptor-mediated activation of MAP kinase. These results demonstrate a novel regulatory action of the androgen receptor and prove that in addition to its known transcriptional effects, it also uses non-conventional means to modulate several cellular signalling processes.
Peterziel
H
H
Forschungszentrum Karlsruhe, Institut für Toxikologie und Genetik, Germany.
Mink
S
S
Schonert
A
A
Becker
M
M
Klocker
H
H
Cato
A C
AC
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000726:Androgen Antagonists / Q000494:pharmacology; D002467:Cell Nucleus / Q000201:enzymology; D003593:Cytoplasm / Q000201:enzymology; D004268:DNA-Binding Proteins; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008024:Ligands; D020935:MAP Kinase Signaling System; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011944:Receptors, Androgen / Q000187:drug effects / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013739:Testosterone; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D050807:ets-Domain Protein Elk-1
D000726:Androgen Antagonists; D004268:DNA-Binding Proteins; D013196:Dihydrotestosterone; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007211:Indoles; D008024:Ligands; D008301:Maleimides; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D011993:Recombinant Fusion Proteins; D013739:Testosterone; D013755:Tetradecanoylphorbol Acetate; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; C494112:ELK1 protein, human; C070515:bisindolylmaleimide I; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one