Target Gene-Specific Regulation of Androgen Receptor Activity by p42/p44 Mitogen-Activated Protein Kinase
Target Gene-Specific Regulation of Androgen Receptor Activity by p42/p44 Mitogen-Activated Protein Kinase
复制标题
DOI：
10.1210/me.2007-0481
复制
发表时间：
2008-11-01
影响因子：
--
通讯作者：
Weigel, Nancy L.
中科院分区：
文献类型：
--
作者：
Agoulnik, Irina U.;Bingman, William E., III;Weigel, Nancy L.
有证据表明雄激素受体（AR）不仅在雄激素依赖性前列腺癌中很重要，而且在对雄激素剥夺治疗产生耐药性的肿瘤中也继续发挥作用，这突出了寻找阻断AR活性的替代方法的必要性。AR是一种激素激活的转录因子，它的辅激活因子是磷蛋白。因此，我们试图确定特定细胞信号通路的抑制是否会降低AR功能。我们发现，无论是通过MAPK激酶抑制剂U0126，还是通过小干扰RNA耗尽激酶，短期抑制p42/p44 MAPK活性，都会导致AR活性的靶基因特异性降低。AR增强了U0126敏感靶基因（包括前列腺特异性抗原和TMPRSS2）的组蛋白H3乙酰化，但不增加U0126耐药PMEPA1基因的组蛋白H3乙酰化。因此，尽管AR诱导了许多靶基因的转录，但AR在染色质水平上诱导的分子变化是靶基因特异性的。U0126长期治疗（24-48小时）导致g1细胞周期阻滞，并通过降低AR mRNA和降低AR蛋白稳定性降低AR表达。因此，降低前列腺癌中p42/p44 MAPK活性的治疗有可能通过降低表达水平以及靶基因选择性抑制AR功能来降低AR活性。（分子内分泌学22:2420-2432,2008）
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 G 1 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. (Molecular Endocrinology 22: 2420-2432, 2008)