Dow L E, Elsum I A, King C L, Kinross K M, Richardson H E, Humbert P O
Research Division, Cell Cycle and Cancer Genetics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Oncogene. 2008 Oct 9;27(46):5988-6001. doi: 10.1038/onc.2008.219. Epub 2008 Jul 21.
Activating mutations in genes of the Ras-mitogen-activated protein kinase (MAPK) pathway occur in approximately 30% of all human cancers; however, mutation of Ras alone is rarely sufficient to induce tumour development. Scribble is a polarity regulator recently isolated from a Drosophila screen for events that cooperate with Ras mutation to promote tumour progression and cell invasion. In mammals, Scribble regulates directed cell migration and wound healing in vivo; however, no role has been identified for mammalian Scribble in oncogenic transformation. Here we show that in human epithelial cells expressing oncogenic Ras or Raf, loss of Scribble promotes invasion of cells through extracellular matrix in an organotypic culture system. Further, we show that the mechanism by which this occurs is in the regulation of MAPK signalling by Scribble. The suppression of MAPK signalling is a highly conserved function of Scribble as it also prevents Raf-mediated defects in Drosophila wing development. Our data identify Scribble as an important mediator of MAPK signalling and provide a molecular basis for the observation that Scribble expression is decreased in many invasive human cancers.
Ras-丝裂原活化蛋白激酶（MAPK）信号通路相关基因的激活突变约发生于30%的人类癌症中；然而，仅Ras突变很少足以诱发肿瘤发展。Scribble是一种极性调节因子，最近从果蝇筛选中分离出来，用于筛选与Ras突变协同促进肿瘤进展和细胞侵袭的事件。在哺乳动物中，Scribble在体内调节定向细胞迁移和伤口愈合；然而，尚未确定哺乳动物Scribble在致癌转化中的作用。在此我们表明，在表达致癌Ras或Raf的人上皮细胞中，Scribble缺失促进细胞在器官型培养系统中通过细胞外基质进行侵袭。此外，我们表明发生这种情况的机制在于Scribble对MAPK信号的调节。MAPK信号的抑制是Scribble的一种高度保守功能，因为它还能预防果蝇翅膀发育中Raf介导的缺陷。我们的数据确定Scribble是MAPK信号的重要调节因子，并为许多侵袭性人类癌症中Scribble表达降低这一观察结果提供了分子基础。
