GRIM-19 mutations fail to inhibit v-Src-induced oncogenesis.
GRIM-19 mutations fail to inhibit v-Src-induced oncogenesis.
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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被证实。v-Src蛋白是Src的致癌突变体，其促进细胞存活、迁移、侵袭和分裂。GRIM-19是使用全基因组敲除筛选分离的抗癌基因。GRIM-19与转录因子STAT 3结合并消除其促癌作用，而v-Src激活STAT 3以促进其致癌作用。然而，我们发现GRIM-19独立于STAT 3抑制v-Src的促癌作用。在这里，我们报告了一组头颈癌患者中功能失活GRIM-19突变的鉴定。虽然野生型GRIM-19强烈消融v-Src诱导的细胞迁移、细胞骨架重塑和肿瘤转移，但肿瘤衍生的突变体（L71 P、L91 P和A95 T）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Pag 1的表达，Pag 1是Src的脂筏相关抑制剂，野生型GRIM-19可恢复Pag 1的表达。肿瘤衍生的突变GRIM-19蛋白未能上调Pag 1。这些研究显示了一种新的机制，可以解除癌细胞中Src活性的调节。
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 anti-oncogene isolated using a genome-wide knockdown screen. 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 (L71P, L91P and A95T) did not. These mutants were also incapable of inhibiting the drug resistance of v-Src-transformed cells. v-Src down regulated 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.
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DOI：
10.1038/nrm3141
发表时间：
2011-06-23
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.3
作者：
Bromberg, JF;Horvath, CM;Darnell, JE
通讯作者：
Darnell, JE
影响因子：
5.3
作者：
Hofman, ER;Boyanapalli, M;Kalvakolanu, DV
通讯作者：
Kalvakolanu, DV
影响因子：
4.8
作者：
Angell, JE;Lindner, DJ;Kalvakolanu, DV
通讯作者：
Kalvakolanu, DV
DOI：
10.1073/pnas.91.9.3984
发表时间：
1994-04-26
影响因子：
11.1
作者：
SABE, H;HATA, A;HANAFUSA, H
通讯作者：
HANAFUSA, H