Yuan M, Tomlinson V, Lara R, Holliday D, Chelala C, Harada T, Gangeswaran R, Manson-Bishop C, Smith P, Danovi S A, Pardo O, Crook T, Mein C A, Lemoine N R, Jones L J, Basu S
Cell Survival Signalling Laboratory, Centre for Molecular Oncology, Institute of Cancer, Charterhouse Square, London, UK.
Cell Death Differ. 2008 Nov;15(11):1752-9. doi: 10.1038/cdd.2008.108. Epub 2008 Jul 11.
Yes-associated protein (YAP) has been shown to positively regulate p53 family members and to be negatively regulated by the AKT proto-oncogene product in promoting apoptosis. On the basis of this function and its location at 11q22.2, a site of frequent loss of heterozygosity (LOH) in breast cancer, we investigated whether YAP is a tumor suppressor in breast. Examination of tumors by immunohistochemistry demonstrated significant loss of YAP protein. LOH analysis revealed that protein loss correlates with specific deletion of the YAP gene locus. Functionally, short hairpin RNA knockdown of YAP in breast cell lines suppressed anoikis, increased migration and invasiveness, inhibited the response to taxol and enhanced tumor growth in nude mice. This is the first report indicating YAP as a tumor suppressor, revealing its decreased expression in breast cancer as well as demonstrating the functional implications of YAP loss in several aspects of cancer signaling.
Yes相关蛋白（YAP）已被证明在促进细胞凋亡过程中正向调节p53家族成员，并受到AKT原癌基因产物的负向调节。基于其功能以及位于11q22.2（乳腺癌中杂合性缺失（LOH）的常见位点）这一位置，我们研究了YAP在乳腺中是否为肿瘤抑制因子。通过免疫组织化学对肿瘤进行检测显示YAP蛋白显著缺失。LOH分析表明蛋白缺失与YAP基因位点的特定缺失相关。在功能上，乳腺细胞系中YAP的短发夹RNA敲低抑制了失巢凋亡，增加了迁移和侵袭能力，抑制了对紫杉醇的反应，并增强了裸鼠体内的肿瘤生长。这是首次表明YAP为肿瘤抑制因子的报告，揭示了其在乳腺癌中表达降低，并证明了YAP缺失在癌症信号传导多个方面的功能影响。
