Target gene-specific regulation of androgen receptor activity by p42/p44 mitogen-activated protein kinase

Mol Endocrinol. 2008 Nov;22(11):2420-32. doi: 10.1210/me.2007-0481. Epub 2008 Sep 11.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Base Sequence
  • Binding Sites / genetics
  • Butadienes / pharmacology
  • Cell Line, Tumor
  • Enhancer Elements, Genetic
  • Histones / chemistry
  • Histones / metabolism
  • Humans
  • MAP Kinase Signaling System
  • Male
  • Mitogen-Activated Protein Kinase 1 / adverse effects
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Nitriles / pharmacology
  • Promoter Regions, Genetic
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Stability
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • RNA, Small Interfering / genetics
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism*


  • Butadienes
  • Histones
  • Nitriles
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • RNA, Neoplasm
  • RNA, Small Interfering
  • Receptors, Androgen
  • U 0126
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3