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Target Gene-Specific Regulation of Androgen Receptor Activity by p42/p44 Mitogen-Activated Protein Kinase

Department of Molecular and Cellular Biology (I.U.A., W.E.B., M.N., W.L., N.L.W.), Duncan Cancer Center (W.L.), and Scott Department of Urology (N.L.W.), Baylor College of Medicine, Houston Texas 77030; Division of Molecular and Cellular Oncology (Q.W., M.B.), Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115; and Department of Biostatistics and Computational Biology (X.L.), Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Nancy L. Weigel, Baylor College of Medicine, One Baylor Plaza, Houston Texas 77030. E-mail: nweigel{at}bcm.tmc.edu.

Evidence that the androgen receptor (AR) is not only important in androgen-dependent prostate cancer, but also continues to play a role in tumors that become resistant to androgen deprivation therapies, highlights the need to find alternate means to block AR activity. AR, a hormone-activated transcription factor, and its coactivators are phosphoproteins. Thus, we sought to determine whether inhibition of specific cell signaling pathways would reduce AR function. We found that short-term inhibition of p42/p44 MAPK activity either by a MAPK kinase inhibitor, U0126, or by depletion of kinase with small interfering RNA caused target gene-specific reductions in AR activity. AR enhances histone H3 acetylation of target genes that are sensitive to U0126 including prostate-specific antigen and TMPRSS2, but does not increase histone H3 acetylation of the U0126-resistant PMEPA1 gene. Thus, although AR induces transcription of many target genes, the molecular changes induced by AR at the chromatin level are target gene specific. Long-term treatment (24–48 h) with U0126 causes a G₁ cell cycle arrest and reduces AR expression both through a decrease in AR mRNA and a reduction in AR protein stability. Thus, treatments that reduce p42/p44 MAPK activity in prostate cancer have the potential to reduce AR activity through a reduction in expression levels as well as by target gene-selective inhibition of AR function.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Coregulators:   SRC-1

Ligands:   R1881

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