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

Publication ,  Journal Article
Agoulnik, IU; Bingman, WE; Nakka, M; Li, W; Wang, Q; Liu, XS; Brown, M; Nancy L., NL
Published in: Molecular Endocrinology
November 1, 2008

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.

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Published In

Molecular Endocrinology

DOI

EISSN

1944-9917

ISSN

0888-8809

Publication Date

November 1, 2008

Volume

22

Issue

11

Start / End Page

2420 / 2432

Publisher

The Endocrine Society

Related Subject Headings

  • Endocrinology & Metabolism
  • 11 Medical and Health Sciences
  • 07 Agricultural and Veterinary Sciences
  • 06 Biological Sciences
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Agoulnik, I. U., Bingman, W. E., Nakka, M., Li, W., Wang, Q., Liu, X. S., … Nancy L., N. L. (2008). Target Gene-Specific Regulation of Androgen Receptor Activity by p42/p44 Mitogen-Activated Protein Kinase. Molecular Endocrinology, 22(11), 2420–2432. https://doi.org/10.1210/me.2007-0481
Agoulnik, Irina U., William E. Bingman, Manjula Nakka, Wei Li, Qianben Wang, X Shirley Liu, Myles Brown, and Nancy L. Nancy L. “Target Gene-Specific Regulation of Androgen Receptor Activity by p42/p44 Mitogen-Activated Protein Kinase.” Molecular Endocrinology 22, no. 11 (November 1, 2008): 2420–32. https://doi.org/10.1210/me.2007-0481.
Agoulnik IU, Bingman WE, Nakka M, Li W, Wang Q, Liu XS, et al. Target Gene-Specific Regulation of Androgen Receptor Activity by p42/p44 Mitogen-Activated Protein Kinase. Molecular Endocrinology. 2008 Nov 1;22(11):2420–32.
Agoulnik, Irina U., et al. “Target Gene-Specific Regulation of Androgen Receptor Activity by p42/p44 Mitogen-Activated Protein Kinase.” Molecular Endocrinology, vol. 22, no. 11, The Endocrine Society, Nov. 2008, pp. 2420–32. Crossref, doi:10.1210/me.2007-0481.
Agoulnik IU, Bingman WE, Nakka M, Li W, Wang Q, Liu XS, Brown M, Nancy L. NL. Target Gene-Specific Regulation of Androgen Receptor Activity by p42/p44 Mitogen-Activated Protein Kinase. Molecular Endocrinology. The Endocrine Society; 2008 Nov 1;22(11):2420–2432.

Published In

Molecular Endocrinology

DOI

EISSN

1944-9917

ISSN

0888-8809

Publication Date

November 1, 2008

Volume

22

Issue

11

Start / End Page

2420 / 2432

Publisher

The Endocrine Society

Related Subject Headings

  • Endocrinology & Metabolism
  • 11 Medical and Health Sciences
  • 07 Agricultural and Veterinary Sciences
  • 06 Biological Sciences