Overholtzer Michael, Zhang Jianmin, Smolen Gromoslaw A, Muir Beth, Li Wenmei, Sgroi Dennis C, Deng Chu-Xia, Brugge Joan S, Haber Daniel A
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12405-10. doi: 10.1073/pnas.0605579103. Epub 2006 Aug 7.
In a screen for gene copy-number changes in mouse mammary tumors, we identified a tumor with a small 350-kb amplicon from a region that is syntenic to a much larger locus amplified in human cancers at chromosome 11q22. The mouse amplicon contains only one known gene, Yap, encoding the mammalian ortholog of Drosophila Yorkie (Yki), a downstream effector of the Hippo(Hpo)-Salvador(Sav)-Warts(Wts) signaling cascade, recently identified in flies as a critical regulator of cellular proliferation and apoptosis. In nontransformed mammary epithelial cells, overexpression of human YAP induces epithelial-to-mesenchymal transition, suppression of apoptosis, growth factor-independent proliferation, and anchorage-independent growth in soft agar. Together, these observations point to a potential oncogenic role for YAP in 11q22-amplified human cancers, and they suggest that this highly conserved signaling pathway identified in Drosophila regulates both cellular proliferation and apoptosis in mammalian epithelial cells.
在一项针对小鼠乳腺肿瘤基因拷贝数变化的筛选中，我们鉴定出一个肿瘤，其具有一个来自与人类癌症中在11q22染色体上扩增的大得多的基因座同线的区域的350 kb小扩增子。小鼠扩增子仅包含一个已知基因Yap，它编码果蝇Yorkie（Yki）的哺乳动物直系同源物，Yki是Hippo（Hpo）-Salvador（Sav）-Warts（Wts）信号级联反应的下游效应物，最近在果蝇中被鉴定为细胞增殖和凋亡的关键调节因子。在未转化的乳腺上皮细胞中，人类YAP的过表达会诱导上皮-间质转化、抑制凋亡、不依赖生长因子的增殖以及在软琼脂中不依赖贴壁的生长。这些观察结果共同表明YAP在11q22扩增的人类癌症中具有潜在的致癌作用，并且它们表明在果蝇中鉴定出的这种高度保守的信号通路调节哺乳动物上皮细胞中的细胞增殖和凋亡。
