ESTROGEN RECEPTOR ALPHA IS A PUTATIVE SUBSTRATE FOR THE BRCA1 UBIQUITIN LIGASE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者的研究机构。 乳腺癌抑制蛋白BRCA 1是一种在广泛组织中表达的泛素连接酶。然而，单个BRCA 1突变的遗传显著增加了女性一生中发生乳腺和卵巢组织特异性癌症的机会。最近，研究表明这种组织特异性可能与BRCA 1抑制雌激素受体（ER）转录激活有关。在这里，我们表明，ER是BRCA 1/BARD 1泛素连接酶的一个假定的底物，提示BRCA 1调节ER活性的可能机制。我们的研究结果表明，ER主要是monoubiquitinated的反应，涉及与BRCA 1和BARD 1的相互作用。ER泛素化所必需的BRCA 1/BARD 1区域分别包括BRCA 1和BARD 1的RING结构域和至少241和170个残基。观察到BRCA 1中的癌症易感突变可消除ER泛素化。ER作为推定的BRCA 1/BARD 1泛素化底物的鉴定揭示了BRCA 1/BARD 1连接酶活性丧失与组织特异性癌之间的潜在联系。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The breast cancer suppressor protein, BRCA1, is a ubiquitin ligase expressed in a wide range of tissues. However, inheritance of a single BRCA1 mutation significantly increases a woman's lifetime chance of developing tissue-specific cancers in the breast and ovaries. Recently, studies have suggested this tissue specificity may be linked to inhibition of estrogen receptor (ER) transcriptional activation by BRCA1. Here, we show that ER is a putative substrate for the BRCA1/BARD1 ubiquitin ligase, suggesting a possible mechanism for regulation of ER activity by BRCA1. Our results show ER is predominantly monoubiquitinated in a reaction that involves interactions with both BRCA1 and BARD1. The regions of BRCA1/BARD1 necessary for ER ubiquitination include the RING domains and at least 241 and 170 residues of BRCA1 and BARD1, respectively. Cancer-predisposing mutations in BRCA1 are observed to abrogate ER ubiquitination. The identification of ER as a putative BRCA1/BARD1 ubiquitination substrate reveals a potential link between the loss of BRCA1/BARD1 ligase activity and tissue-specific carcinoma.