p300 Modulates the BRCA1 inhibition of estrogen receptor activity.
p300 Modulates the BRCA1 inhibition of estrogen receptor activity.
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发表时间：
2002
期刊：
影响因子：
11.2
通讯作者：
S. Fan;Yongxian Ma;Chenguang Wang;R. Yuan;Q. Meng;Ji‐an Wang;M. Erdos;I. Goldberg;P. Webb;P. Kushner;R. Pestell;E. Rosen
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文献类型：
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作者：
S. Fan;Yongxian Ma;Chenguang Wang;R. Yuan;Q. Meng;Ji‐an Wang;M. Erdos;I. Goldberg;P. Webb;P. Kushner;R. Pestell;E. Rosen
我们先前报道，乳腺癌易感基因BRCA1的表达强烈地抑制了人乳腺和前列腺癌细胞系中雌激素受体(ER-α)的转录活性，但仅微弱地抑制了宫颈癌细胞中ER-α的活性(S.Fan等人，Science(华盛顿)。DC)，284：1354-1356,1999)。我们现在报道，BRCA1抑制ER-α活性的能力与其诱导乳腺和前列腺中转录辅助激活因子p300的细胞水平下调有关，但与宫颈癌细胞中的水平无关。另一方面，BRCA1未能改变CREB结合蛋白(CBP)在任何一种细胞类型中的表达，CREB结合蛋白是p300的结构和功能同源物。P300或CBP的异位表达“挽救”(即逆转)了BRCA1对ER-α活性的抑制，而另外两个核受体共激活因子p300/CBP相关因子(PCAF)和糖皮质激素受体相互作用蛋白-1(GRIP1)未能挽救ER-α的活性。救援功能定位于富含半胱氨酸-组氨酸的结构域CH3，我们发现p300/CBP的一个区域直接与ER-α保守的COOH末端激活结构域(AF-2)相互作用。P300和ER-α也被发现在体内相互作用，并共同定位于乳腺癌细胞的细胞核内。这些发现表明，辅因子p300和CBP调节BRCA1蛋白抑制ER-α信号转导的能力。他们进一步表明，BRCA1抑制ER-α活性可能至少部分归因于p300的下调。
We previously reported that expression of the breast cancer susceptibility gene BRCA1 strongly inhibits the transcriptional activity of the estrogen receptor (ER-alpha) in human breast and prostate cancer cell lines but only weakly inhibits ER-alpha activity in cervical cancer cells (S. Fan et al., Science (Wash. DC), 284: 1354-1356, 1999). We now report that the ability of BRCA1 to repress ER-alpha activity correlates with its ability to induce down-regulation of the cellular levels of the transcriptional coactivator p300 in breast and prostate, but not in cervical cancer cells. On the other hand, BRCA1 failed to alter the expression of the CREB binding protein (CBP), the structural and functional homologue of p300, in any of these cell types. Ectopic expression of either p300 or CBP "rescued" (i.e., reversed) the BRCA1 inhibition of ER-alpha activity, whereas two other nuclear receptor coactivators, the p300/CBP-associated factor (PCAF) and the glucocorticoid receptor-interacting protein-1 (GRIP1), failed to rescue the ER-alpha activity. The rescue function mapped to the cysteine-histidine rich domain CH3, a region of p300/CBP that we found to interact directly with the conserved COOH-terminal activation domain (AF-2) of ER-alpha. p300 and ER-alpha were also found to interact in vivo and to colocalize within the nucleus in breast cancer cells. These findings suggest that the cofactors p300 and CBP modulate the ability of the BRCA1 protein to inhibit ER-alpha signaling. They further suggest that the BRCA1 inhibition of ER-alpha activity may be attributable, at least in part, to the down-regulation of p300.