c-Jun enhancement of androgen receptor transactivation is associated with prostate cancer cell proliferation
c-Jun enhancement of androgen receptor transactivation is associated with prostate cancer cell proliferation
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DOI：
10.1038/sj.onc.1209705
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发表时间：
2006-11-01
期刊：
影响因子：
8
通讯作者：
Shemshedini, L.
中科院分区：
文献类型：
--
作者：
Chen, S-Y;Cai, C.;Shemshedini, L.
雄激素和雄激素受体(AR)参与前列腺癌的生长和发展。我们以前的研究表明，原癌蛋白c-jun是一种AR共激活因子，通过介导受体二聚化和随后的DNA结合来刺激AR的反式激活。为了研究这种c-jun活性与AR的生理相关性，我们建立了稳定的表达不同水平c-jun的LNCaP细胞系。这些细胞系表现出内源性c-jun水平与AR转录活性和内源性雄激素调节基因表达之间的直接相关性。反义RNA阻断LNCaP细胞内源性c-jun的表达，强烈影响这些细胞的雄激素依赖的增殖。相反，c-jun突变体的表达显著增强了雄激素依赖的增殖。c-jun突变体在AR的共激活中完全活跃，但在AP-1反式激活中缺失。这。Nding结果表明，c-jun的共激活功能足以调节雄激素诱导的LNCaP细胞的生长。C-jun还增强了雄激素非依赖性LNCaP细胞的AR反式激活，LNCaP细胞在基因表达和生长行为上与激素不耐药的前列腺癌细胞非常相似。重要的是，siRNA介导的内源性c-jun表达的抑制导致这些细胞的生长显著减少，强烈表明c-jun在激素非依赖性前列腺癌中起着重要的生物学作用。
Androgens and the androgen receptor (AR) are involved in the growth and progression of prostate cancer. Our previous studies suggest that the proto-oncoprotein c-Jun is an AR coactivator that stimulates AR transactivation by mediating receptor dimerization and subsequent DNA binding. To study the physiological relevance of this c-Jun activity on AR, we have generated stable LNCaP cell lines expressing different levels of c-Jun. These cell lines exhibit a direct correlation between endogenous c-Jun levels and AR transcriptional activity and expression of endogenous androgen-regulated genes. Disruption by antisense RNA of endogenous c-Jun expression in LNCaP cells strongly compromises the androgen-dependent proliferation of these cells. In contrast, expression of a c-Jun mutant, which is fully active in coactivation of AR but deficient in AP-1 transactivation, significantly enhances androgen-dependent proliferation. This. nding indicates that the coactivation function of c-Jun is sufficient for regulating androgen-induced growth of LNCaP cells. c-Jun also enhances AR transactivtion in androgen-independent LNCaP cells, which closely mimic hormone-refractory prostate cancer cells in gene expression and growth behavior. Importantly, siRNA-mediated repression of endogenous c-Jun expression results in markedly reduced growth of these cells, strongly suggesting an important biological role for c-Jun in hormone-efractory prostate cancer.