Stasinopoulos Ioannis A, Mironchik Yelena, Raman Ana, Wildes Flonne, Winnard Paul, Raman Venu
Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
J Biol Chem. 2005 Jan 21;280(3):2294-9. doi: 10.1074/jbc.M411018200. Epub 2004 Nov 15.
The homeotic gene HOXA5 has been shown to play an important role in breast tumorigenesis. We have shown that loss of p53 correlated with loss of a developmentally regulated transcription factor, HOXA5, in primary breast cancer. Searching for potential protein interacting partners we found that HOXA5 binds to an anti-apoptotic protein, Twist. Furthermore, Twist-overexpressing MCF-7 cells displayed a deregulated p53 response to gamma-radiation and decreased regulation of downstream target genes. Using a p53-promoter-reporter system, we demonstrated that HOXA5 could partially restore the inhibitory effects of Twist on p53 target genes. These effects are likely mediated through both the transcriptional up-regulation of p53 and the protein-protein interaction between HOXA5 and Twist. Thus, the loss of HOXA5 expression could lead to the functional activation of Twist resulting in aberrant cell cycle regulation and promoting breast carcinogenesis.
同源异型基因HOXA5已被证明在乳腺肿瘤发生中起重要作用。我们已经表明，在原发性乳腺癌中，p53的缺失与一种发育调控转录因子HOXA5的缺失相关。在寻找潜在的蛋白质相互作用伙伴时，我们发现HOXA5与一种抗凋亡蛋白Twist结合。此外，过表达Twist的MCF-7细胞对γ射线显示出p53反应失调，并且下游靶基因的调控减弱。使用p53启动子报告系统，我们证明HOXA5可以部分恢复Twist对p53靶基因的抑制作用。这些作用可能是通过p53的转录上调以及HOXA5与Twist之间的蛋白质-蛋白质相互作用介导的。因此，HOXA5表达的缺失可能导致Twist的功能激活，从而导致异常的细胞周期调控并促进乳腺癌的发生。
