Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Oncogene. 2009 Dec 17;28(50):4469-79. doi: 10.1038/onc.2009.270. Epub 2009 Oct 26.
The Lats2 tumor suppressor protein has been implicated earlier in promoting p53 activation in response to mitotic apparatus stress, by preventing Mdm2-driven p53 degradation. We now report that Lats2 also has a role in an ATR-Chk1-mediated stress check point in response to oncogenic H-Ras. Activated mutant H-Ras triggers the translocation of Lats2 from centrosomes into the nucleus, coupled with an increase in Lats2 protein levels. This leads to the induction of p53 activity, upregulation of proapoptotic genes, downregulation of antiapoptotic genes and eventually apoptotic cell death. Many of the cells that survive apoptosis undergo senescence. However, a fraction of the cells escape this checkpoint mechanism, despite maintaining a high mutant H-Ras expression. These escapers display increased genome instability, as evidenced by a substantial fraction of cells with micronuclei and cells with polyploid genomes. Interestingly, such cells show markedly reduced levels of Lats2, in conjunction with enhanced hypermethylation of the Lats2 gene promoter. Our findings suggest that Lats2 might have an important role in quenching H-Ras-induced transformation, whereas silencing of Lats2 expression might serve as a mechanism to enable tumor progression.
Lats2 肿瘤抑制蛋白先前被发现在有丝分裂器应激下通过阻止 Mdm2 驱动的 p53 降解来促进 p53 的激活。我们现在报告 Lats2 也在 ATR-Chk1 介导的应激检查点中发挥作用，以响应致癌性 H-Ras。激活的突变型 H-Ras 触发 Lats2 从中心体向核内易位，同时 Lats2 蛋白水平增加。这导致 p53 活性的诱导、促凋亡基因的上调、抗凋亡基因的下调，最终导致细胞凋亡。许多凋亡的细胞会经历衰老。然而，尽管维持高突变型 H-Ras 表达，仍有一部分细胞逃避了这种检查点机制。这些逃逸细胞表现出更高的基因组不稳定性，这表现在大量带有微核的细胞和具有多倍体基因组的细胞。有趣的是，这些细胞的 Lats2 水平明显降低，同时 Lats2 基因启动子的超甲基化增强。我们的研究结果表明，Lats2 可能在抑制 H-Ras 诱导的转化中具有重要作用，而 Lats2 表达的沉默可能是促进肿瘤进展的一种机制。
