p53-mediated activation of the mitochondrial protease HtrA2/Omi prevents cell invasion.
p53-mediated activation of the mitochondrial protease HtrA2/Omi prevents cell invasion.
复制标题
DOI：
10.1083/jcb.201309107
复制
发表时间：
2014-03-31
期刊：
影响因子：
--
通讯作者：
Kawauchi K
中科院分区：
文献类型：
--
作者：
Yamauchi S;Hou YY;Guo AK;Hirata H;Nakajima W;Yip AK;Yu CH;Harada I;Chiam KH;Sawada Y;Tanaka N;Kawauchi K
抑癌基因P53通过调节肌动蛋白细胞骨架，诱导线粒体蛋白HtrA2/Omi的激活，阻止RAS的侵袭。致癌RAS可诱导细胞转化并促进侵袭性表型。抑癌基因P53在RAS诱导的侵袭过程中起抑制作用。然而，其机制仍鲜为人知。在这里，我们表明，p53诱导激活线粒体蛋白酶高温要求A2(HtrA2；也称为Omi)，并通过调节肌动蛋白细胞骨架来防止RAS驱动的侵袭。癌基因RAS增加P53在细胞质中的积聚，促进p38丝裂原活化蛋白激酶(MAPK)转位到线粒体，并诱导HtrA2/Omi的磷酸化。同时，致癌RAS还诱导线粒体碎裂，而与P53的表达无关，导致HtrA2/Omi从线粒体释放到胞浆中。因此，磷酸化的htrA2/Omi裂解β-肌动蛋白，减少胞浆中丝状肌动蛋白(F-肌动蛋白)的数量。这最终下调p130Crk相关底物(P130Cas)介导的片状脂肪形成，对抗致癌RAS启动的侵袭性表型。我们的新发现为P53阻止转化细胞恶性进展的机制提供了洞察力。
The tumor suppressor p53 induces activation of the mitochondrial protease HtrA2/Omi and prevents Ras-driven invasion by modulating the actin cytoskeleton. Oncogenic Ras induces cell transformation and promotes an invasive phenotype. The tumor suppressor p53 has a suppressive role in Ras-driven invasion. However, its mechanism remains poorly understood. Here we show that p53 induces activation of the mitochondrial protease high-temperature requirement A2 (HtrA2; also known as Omi) and prevents Ras-driven invasion by modulating the actin cytoskeleton. Oncogenic Ras increases accumulation of p53 in the cytoplasm, which promotes the translocation of p38 mitogen-activated protein kinase (MAPK) into mitochondria and induces phosphorylation of HtrA2/Omi. Concurrently, oncogenic Ras also induces mitochondrial fragmentation, irrespective of p53 expression, causing the release of HtrA2/Omi from mitochondria into the cytosol. Phosphorylated HtrA2/Omi therefore cleaves β-actin and decreases the amount of filamentous actin (F-actin) in the cytosol. This ultimately down-regulates p130 Crk-associated substrate (p130Cas)-mediated lamellipodia formation, countering the invasive phenotype initiated by oncogenic Ras. Our novel findings provide insights into the mechanism by which p53 prevents the malignant progression of transformed cells.
登录
查看更多内容
影响因子：
9.2
作者：
De Vos, KJ;Allan, VJ;Sheetz, MP
通讯作者：
Sheetz, MP
影响因子：
21.3
作者：
Kawauchi, Keiko;Araki, Keigo;Tanaka, Nobuyuki
通讯作者：
Tanaka, Nobuyuki
影响因子：
64.8
作者：
Green, Douglas R.;Kroemer, Guido
通讯作者：
Kroemer, Guido
DOI：
10.1083/jcb.201009059
发表时间：
2011-01-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Muller PA;Vousden KH;Norman JC
通讯作者：
Norman JC
影响因子：
16
作者：
Nakano, K;Vousden, KH
通讯作者：
Vousden, KH