GRIM-19 inhibits v-Src-induced cell motility by interfering with cytoskeletal restructuring.
GRIM-19 inhibits v-Src-induced cell motility by interfering with cytoskeletal restructuring.
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DOI：
10.1038/onc.2008.480
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发表时间：
2009-03-12
期刊：
影响因子：
8
通讯作者：
Kalvakolanu, D. V.
中科院分区：
文献类型：
--
作者：
Sun, P.;Nallar, S. C.;Kalakonda, S.;Lindner, D. J.;Martin, S. S.;Kalvakolanu, D. V.
GRIM-19(视黄醇-干扰素诱导死亡相关基因19)是受干扰素/维甲酸联合调控的一种新的肿瘤抑制因子。我们最近发现GRIM-19抑制v-Src诱导的细胞的致癌转化和转移行为。致癌的v-Src通过细胞骨架重塑，特别是足小体的形成，诱导细胞运动。在这里，我们发现GRIM-19通过抑制细胞骨架重塑，即足小体的形成，来抑制v-Src诱导的细胞运动。我们还发现GRIM-19的N末端在这一过程中发挥了重要作用，并确定了该区域的关键残基。更重要的是，我们发现肿瘤相关的GRIM-19突变破坏了其抑制v-Src诱导的细胞运动的能力。这些作用似乎独立于STAT3发生，STAT3是GRIM-19介导的抑制作用的已知靶点。最后，肿瘤相关的GRIM-19突变体在体内显著丧失了控制v-Src诱导的转移的能力，这表明了这些观察的生物学和病理学意义。
GRIM-19 (Gene associated with Retinoid-Interferon-induced Mortality 19) is a novel tumor suppressor regulated by Interferon/retinoid combination. We have recently shown that GRIM-19 inhibits v-Src-induced oncogenic transformation and metastatic behavior of cells. Oncogenic v-Src induces cell motility by cytoskeletal remodeling especially the formation of podosomes and. Here we show that GRIM-19 inhibited the v-Src-induced cell motility by inhibiting cytoskeletal remodeling i.e., podosome formation. We also show that the N-terminus of GRIM-19 played a major role in this process and identified critical residues in this region. More importantly, we show that tumor-associated GRIM-19 mutations disrupted its ability to inhibit v-Src-induced cell motility. These actions appear to occur independently of STAT3, a known target of GRIM-19-mediated inhibition. Lastly, tumor-associated GRIM-19 mutants significantly lost their ability to control v-Src-induced metastases in vivo, indicating the biological and pathological significance of these observations.
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