Fabbro Megan, Henderson Beric R
Westmead Institute for Cancer Research, University of Sydney, Westmead Millennium Institute at Westmead Hospital, Darcy Road, P.O. Box 412, Westmead, NSW 2145, Australia.
Cancer Lett. 2008 May 18;263(2):189-96. doi: 10.1016/j.canlet.2008.01.001. Epub 2008 Feb 20.
BRCA1 regulates gene transcription as part of its tumor suppressor function. Prior studies on BRCA1 transactivation did not account for the impact of its binding partner, BARD1. Here we tested the effect of BARD1 on BRCA1 transactivation of the p21 and Gadd45 promoters. We show that BARD1 promoted nuclear accumulation of BRCA1, but repressed BRCA1-mediated transactivation by up to 75% in transfected cells normalized for nuclear BRCA1 levels. The BRCA1 (C61G) RING mutant transactivation function was not regulated by BARD1. We propose that BARD1 reduces BRCA1 transcriptional activity, and that this at least partly involves BRCA1/BARD1 E3 ubiquitin ligase activity, which is disrupted by the C61G mutation.
BRCA1作为其肿瘤抑制功能的一部分，调控基因转录。先前关于BRCA1反式激活的研究未考虑其结合伴侣BARD1的影响。在此，我们测试了BARD1对BRCA1激活p21和Gadd45启动子的影响。我们发现，BARD1促进BRCA1的核内积累，但在针对核内BRCA1水平进行标准化的转染细胞中，BARD1可将BRCA1介导的反式激活抑制高达75%。BRCA1 (C61G) RING突变体的反式激活功能不受BARD1调控。我们提出，BARD1降低了BRCA1的转录活性，并且这至少部分涉及BRCA1/BARD1 E3泛素连接酶活性，而C61G突变会破坏该活性。
