TAF1 Differentially Enhances Androgen Receptor Transcriptional Activity via Its N-Terminal Kinase and Ubiquitin-Activating and -Conjugating Domains
TAF1 Differentially Enhances Androgen Receptor Transcriptional Activity via Its N-Terminal Kinase and Ubiquitin-Activating and -Conjugating Domains
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DOI：
10.1210/me.2009-0229
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发表时间：
2010-04-01
影响因子：
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通讯作者：
Rennie, Paul S.
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文献类型：
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作者：
Tavassoli, Peyman;Wafa, Latif A.;Rennie, Paul S.
雄激素受体（AR）辅助调节因子的异常表达与前列腺癌进展至去势抵抗有关。利用阻遏型反式激活蛋白酵母双杂交系统，我们发现TATA结合蛋白相关因子1（TAF1）与AR相互作用。在组织微阵列中，TAF1显示随着新辅助雄激素戒断的持续时间和去势抵抗的进展而稳定增加。谷胱甘肽S-转移酶下拉试验证实TAF1通过其乙酰化和泛素激活/缀合结构域（E1/E2）直接结合到AR N末端。免疫共沉淀和ChIP分析显示，TAF1和AR在前列腺癌细胞中的前列腺特异性抗原启动子/增强子上共定位。关于AR活性的调节，TAF1的过表达增强AR活性数倍，而TAF1的小干扰RNA敲低显著降低AR反式激活。虽然全长TAF1表现出增强AR和一些通用基因的转录活性，选择性AR辅激活因子活性TAF1证明在反式激活实验中使用克隆的N-末端激酶和E1/E2功能域。在保持与AR共激活的泛素激活和共轭结构域，TAF1被发现大大增加了细胞的量的多聚泛素化的AR。总之，我们的研究结果表明，TAF1表达增加与人类前列腺癌进展到致命的去势抵抗状态有关。由于TAF1是AR的共激活因子，结合并增强AR转录活性，因此其过表达可能是癌细胞适应的补偿机制的一部分，以克服循环雄激素水平的降低。（分子内分泌学24：696 - 708，2010）
Aberrant expression of androgen receptor (AR) coregulators has been linked to progression of prostate cancers to castration resistance. Using the repressed transactivator yeast two-hybrid system, we found that TATA binding protein-associated factor 1 (TAF1) interacted with the AR. In tissue microarrays, TAF1 was shown to steadily increase with duration of neoadjuvant androgen withdrawal and with progression to castration resistance. Glutathione S-transferase pulldown assays established that TAF1 bound through its acetylation and ubiquitin-activating/conjugating domains (E1/E2) directly to the AR N terminus. Coimmunoprecipitation and ChIP assays revealed colocalization of TAF1 and AR on the prostate-specific antigen promoter/enhancer in prostate cancer cells. With respect to modulation of AR activity, overexpression of TAF1 enhanced AR activity severalfold, whereas small interfering RNA knockdown of TAF1 significantly decreased AR transactivation. Although full-length TAF1 showed enhancement of both AR and some generic gene transcriptional activity, selective AR coactivator activity by TAF1 was demonstrated in transactivation experiments using cloned N-terminal kinase and E1/E2 functional domains. In keeping with AR coactivation by the ubiquitin-activating and -conjugating domain, TAF1 was found to greatly increase the cellular amount of polyubiquitinated AR. In conclusion, our results indicate that increased TAF1 expression is associated with progression of human prostate cancers to the lethal castration-resistant state. Because TAF1 is a coactivator of AR that binds and enhances AR transcriptional activity, its overexpression could be part of a compensatory mechanism adapted by cancer cells to overcome reduced levels of circulating androgens. (Molecular Endocrinology 24: 696-708, 2010)