CR6-interacting factor 1 represses the transactivation of androgen receptor by direct interaction
CR6-interacting factor 1 represses the transactivation of androgen receptor by direct interaction
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DOI：
10.1210/me.2007-0194
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发表时间：
2008-01-01
影响因子：
--
通讯作者：
Lee, Keesook
中科院分区：
文献类型：
--
作者：
Suh, Ji Ho;Shong, Minho;Lee, Keesook
CR 6相互作用因子1（CRIF 1）先前被鉴定为与Gadd 45家族成员相互作用的核蛋白，并在细胞生长中起负调节剂的作用。然而，CRIF 1的核功能在很大程度上仍然未知。在这项研究中，我们证明CRIF 1作为一种新的辅抑制剂的雄激素受体（AR）在前列腺细胞。瞬时转染研究表明，CRIF 1以剂量依赖性方式特异性抑制靶启动子的AR转录激活。此外，CRIF 1与AR一起募集到内源性AR靶启动子。体内和体外蛋白质相互作用试验表明，CRIF 1通过AR的激活功能-1结构域与AR直接相互作用。有趣的是，CRIF 1的N-末端和C-末端半区都能够独立地与AR相互作用并抑制AR的反式激活。CRIF 1通过与AR共激活因子竞争来抑制AR反式激活。此外，CRIF 1介导的AR反式激活抑制涉及组蛋白去乙酰化酶4的募集。通过小干扰RNA下调CRIF 1增加AR的反式激活和AR靶基因前列腺特异性抗原的mRNA水平，而CRIF 1的过表达降低前列腺特异性抗原mRNA水平。最后，CRIF 1的过表达抑制前列腺癌细胞的雄激素诱导的增殖和细胞周期进展。综上所述，这些结果表明，CRIF 1作为AR辅抑制因子，可能在调节前列腺癌的AR阳性生长中发挥重要作用。
CR6-interacting factor 1 (CRIF1) was previously identified as a nuclear protein that interacts with members of the Gadd45 family and plays a role as a negative regulator in cell growth. However, the nuclear function of CRIF1 remains largely unknown. In this study, we demonstrate that CRIF1 acts as a novel corepressor of the androgen receptor (AR) in prostatic cells. Transient transfection studies show that CRIF1 specifically represses AR transcriptional activation of target promoters in a dose-dependent manner. Additionally, CRIF1 is recruited with AR to the endogenous AR target promoters. In vivo and in vitro protein interaction assays reveal that CRIF1 directly interacts with AR via the activation function-1 domain of AR. Interestingly, both the N-terminal and C-terminal halfregions of CRIF1 are independently capable of interacting with and repressing the transactivation of AR. CRIF1 represses AR transactivation through competition with AR coactivators. In addition, the CRIF1-mediated inhibition of AR transactivation involves the recruitment of histone deacetylase 4. Down-regulation of CRIF1 by small interfering RNA increases the transactivation of AR and the mRNA level of the AR target gene prostate-specific antigen, whereas the overexpression of CRIF1 decreases the prostate-specific antigen mRNA level. Finally, the overexpression of CRIF1 inhibits the androgen-induced proliferation and cell cycle progression of prostate cancer cells. Taken together, these results suggest that CRIF1 acts as an AR corepressor and may play an important role in the regulation of AR-positive growth of prostate cancer.