Department of Microbiology & Immunology, Program in Oncology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
Taussig Cancer Center, Cleveland, OH, USA.
Oncogene. 2014 Jun 12;33(24):3195-204. doi: 10.1038/onc.2013.271. Epub 2013 Jul 15.
The non-receptor tyrosine kinase Src is a major player in multiple physiological responses including growth, survival and differentiation. Overexpression and/or oncogenic mutation in the Src gene have been documented in human tumors. The v-Src protein is an oncogenic mutant of Src, which promotes cell survival, migration, invasion and division. GRIM-19 is an antioncogene isolated using a genome-wide knockdown screen. Genes associated with Retinoid-IFN-induced Mortality (GRIM)-19 binds to transcription factor STAT3 and ablates its pro-oncogenic effects while v-Src activates STAT3 to promote its oncogenic effects. However, we found that GRIM-19 inhibits the pro-oncogenic effects of v-Src independently of STAT3. Here, we report the identification of functionally inactivating GRIM-19 mutations in a set of head and neck cancer patients. While wild-type GRIM-19 strongly ablated v-Src-induced cell migration, cytoskeletal remodeling and tumor metastasis, the tumor-derived mutants (L(71)P, L(91)P and A(95)T) did not. These mutants were also incapable of inhibiting the drug resistance of v-Src-transformed cells. v-Src downregulated the expression of Pag1, a lipid raft-associated inhibitor of Src, which was restored by wild-type GRIM-19. The tumor-derived mutant GRIM-19 proteins failed to upregulate Pag1. These studies show a novel mechanism that deregulates Src activity in cancer cells.
非受体酪氨酸激酶Src 是多种生理反应的主要参与者，包括生长、存活和分化。Src 基因的过表达和/或致癌突变已在人类肿瘤中得到证实。v-Src 蛋白是 Src 的致癌突变体，可促进细胞存活、迁移、侵袭和分裂。GRIM-19 是使用全基因组敲低筛选分离得到的抑癌基因。与视黄酸-IFN 诱导的死亡率（GRIM）-19 相关的基因与转录因子 STAT3 结合，并消除其致癌作用，而 v-Src 激活 STAT3 以促进其致癌作用。然而，我们发现 GRIM-19 独立于 STAT3 抑制 v-Src 的致癌作用。在这里，我们报告了一组头颈部癌症患者中存在功能失活的 GRIM-19 突变。野生型 GRIM-19 强烈抑制 v-Src 诱导的细胞迁移、细胞骨架重塑和肿瘤转移，而肿瘤衍生的突变体（L(71)P、L(91)P 和 A(95)T）则没有。这些突变体也不能抑制 v-Src 转化细胞的耐药性。v-Src 下调了脂质筏相关 Src 抑制剂 Pag1 的表达，而野生型 GRIM-19 则恢复了 Pag1 的表达。肿瘤衍生的突变体 GRIM-19 蛋白未能上调 Pag1。这些研究表明了一种新型机制，可在癌细胞中调节 Src 活性。
