Androgen regulates Cdc6 transcription through interactions between androgen receptor and E2F transcription factor in prostate cancer cells
Androgen regulates Cdc6 transcription through interactions between androgen receptor and E2F transcription factor in prostate cancer cells
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DOI：
10.1016/j.bbamcr.2008.05.006
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发表时间：
2008-10-01
影响因子：
5.1
通讯作者：
Chakrabarti, Ratna
中科院分区：
文献类型：
--
作者：
Mallik, Ipsita;Davila, Monica;Chakrabarti, Ratna
雄激素受体在前列腺癌的发展和维持中起着关键作用。早些时候，我们已经表明，Cdc 6，启动DNA复制的调节蛋白，在雄激素不敏感的前列腺癌细胞下调。在这份报告中，我们研究了雄激素的参与，通过雄激素受体（AR）介导的调节Cdc 6的表达。我们的研究结果表明，雄激素治疗刺激Cdc 6在异种移植肿瘤和雄激素敏感的前列腺癌细胞的表达。我们还表明，雄激素治疗刺激Cdc 6转录通过可能的相互作用的AR与ARE序列中的Cdc 6启动子和雄激素的刺激作用需要完整的E2 F结合位点的启动子。雄激素治疗差异改变E2 F1和E2 F3的核可用性，并以时间依赖性方式增加细胞核中低磷酸化视网膜母细胞瘤蛋白（pRb）的量。我们进一步表明，AR与E2 F转录因子以配体非依赖性方式相互作用，并且配体结合的AR与E2 F蛋白相互作用的效率较低。DNA-蛋白质相互作用分析表明，雄激素治疗改变了前列腺癌细胞中E2 F1与Cdc 6启动子的结合。我们的结论是，AR调节Cdc 6转录通过与Cdc 6启动子的相互作用，并与E2 F1和E2 F3以不同的方式形成复合物。(c)2008 Elsevier B. V.保留所有权利。
Androgen receptor plays a critical role in the development and maintenance of cancers in the prostate. Earlier, we have shown that Cdc6, a regulatory protein for initiation of DNA replication, is down regulated in androgen-insensitive prostate cancer cells. In this report, we studied the involvement of androgen, mediated through androgen receptor (AR) in regulation of Cdc6 expression. Our results demonstrated that androgen treatment stimulated Cdc6 expression in xenograft tumors and androgen-sensitive prostate cancer cells. We also showed that androgen treatment stimulated Cdc6 transcription through possible interaction of AR with the ARE sequence in the Cdc6 promoter and that the stimulatory effect of androgen required intact E2F binding sites in the promoter. Androgen treatment differentially altered nuclear availability of E2F1 and E2F3, and increased the amount of hypophosphorylated retinoblastoma protein (pRb) in the nucleus in a time dependent fashion. We further showed that AR interacted with E2F transcription factors in a ligand-independent manner and that ligand-bound AR was less efficient in interacting with E2F proteins. DNA-protein interaction assays indicated that androgen treatment altered binding of E2F1 to the Cdc6 promoter in prostate cancer cells. We conclude that AR regulates Cdc6 transcription through interaction with the Cdc6 promoter, and complex formation with E2F1 and E2F3 in a differential manner. (c) 2008 Elsevier B.V. All rights reserved.