FoxO1 Mediates PTEN Suppression of Androgen Receptor N- and C-Terminal Interactions and Coactivator Recruitment
FoxO1 Mediates PTEN Suppression of Androgen Receptor N- and C-Terminal Interactions and Coactivator Recruitment
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DOI：
10.1210/me.2008-0147
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发表时间：
2009-02-01
影响因子：
--
通讯作者：
Bai, Wenlong
中科院分区：
文献类型：
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作者：
Ma, Qiuping;Fu, Wei;Bai, Wenlong
FoxO（哺乳动物叉头亚类O）蛋白是作用于PTEN（10号染色体上缺失的磷酸酶和张力蛋白同源物）肿瘤抑制因子下游的转录因子。其活性受AKT介导的磷酸化负调控。我们以前的研究表明，雄激素受体（AR）的转录活性被抑制的PTEN在AKT敏感的方式。在这里，我们报告的全长AR和其N-末端结构域的FoxO 1和参与的FoxO 1在AR抑制PTEN的活动的镇压。活性FoxO 1的异位表达降低了AR的转录活性以及雄激素诱导的细胞增殖和前列腺特异性抗原的产生。通过RNA干扰敲低FoxO 1增加了PTEN完整细胞中AR的转录活性，并减轻了PTEN缺失细胞中异位PTEN对其的抑制。突变分析表明，FoxO 1片段150-655，其中包含叉头盒和C-末端激活结构域，是AR抑制所必需的。哺乳动物的双杂交和谷胱甘肽-S-转移酶下拉试验表明，通过FoxO 1的PTEN的AR活性的抑制涉及干扰雄激素诱导的相互作用的N-和C-末端的AR和招聘的p160辅激活剂的N末端和天然AR靶基因的雄激素反应元件。这些研究揭示了PTEN-FoxO轴抑制AR活性的新机制，并建立FoxO蛋白作为介导前列腺癌细胞中AR和PTEN肿瘤抑制因子之间相互拮抗作用的重要核因子。（分子内分泌学23：213-225，2009）
FoxO (mammalian forkhead subclass O) proteins are transcription factors acting downstream of the PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor. Their activity is negatively regulated by AKT-mediated phosphorylation. Our previous studies showed that the transcriptional activity of the androgen receptor (AR) was inhibited by PTEN in an AKT-sensitive manner. Here, we report the repression of the activity of the full-length AR and its N-terminal domain by FoxO1 and the participation of FoxO1 in AR inhibition by PTEN. Ectopic expression of active FoxO1 decreased the transcriptional activity of AR as well as androgen-induced cell proliferation and production of prostate-specific antigen. FoxO1 knock down by RNA interference increased the transcriptional activity of the AR in PTEN-intact cells and relieved its inhibition by ectopic PTEN in PTEN-null cells. Mutational analysis revealed that FoxO1 fragment 150-655, which contains the forkhead box and C-terminal activation domain, was required for AR inhibition. Mammalian two-hybrid and glutathione-S-transferase pull-down assays demonstrated that the inhibition of AR activity by PTEN through FoxO1 involved the interference of androgen-induced interaction of the N- and C-termini of the AR and the recruitment of the p160 coactivators to its N terminus and to the androgen response elements of natural AR target genes. These studies reveal new mechanisms for the inhibition of AR activity by PTEN-FoxO axis and establish FoxO proteins as important nuclear factors that mediate the mutual antagonism between AR and PTEN tumor suppressor in prostate cancer cells. (Molecular Endocrinology 23: 213-225, 2009)