RASSF7 negatively regulates pro-apoptotic JNK signaling by inhibiting the activity of phosphorylated-MKK7
RASSF7 negatively regulates pro-apoptotic JNK signaling by inhibiting the activity of phosphorylated-MKK7
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DOI：
10.1038/cdd.2010.137
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发表时间：
2011-04-01
影响因子：
12.4
通讯作者：
Katada, T.
中科院分区：
文献类型：
--
作者：
Takahashi, S.;Ebihara, A.;Katada, T.
Ras相关结构域家族（RASSF）的成员影响细胞凋亡和细胞周期，但其机制知之甚少。在这里，我们发现RASSF 7与N-Ras和丝裂原活化蛋白激酶激酶7（MKK 7）相互作用，以负调节c-Jun N-末端激酶（JNK）信号传导。在通过RNAi敲低去除RASSF 7或N-Ras的细胞中，应激诱导的JNK活化和凋亡显著增强。与RASSF 7的相互作用促进了MKK 7的磷酸化状态，但抑制了该激酶激活JNK的能力。RASSF 7需要其RA结构域与GTP结合的N-Ras相互作用和对应激刺激的抗凋亡反应。然而，在长时间的应激后，RASSF 7的抗凋亡作用被消除，因为RASSF 7蛋白通过泛素-蛋白酶体途径降解。我们的研究结果表明，RASSF 7与N-Ras共同作用，构成了一种应激敏感的凋亡调节临时机制。在初始应激下，RASSF 7/N-Ras通过抑制MKK 7/JNK通路促进细胞存活。然而，随着长时间的应激，RASSF 7蛋白会发生降解，从而允许细胞死亡信号继续进行。我们的研究结果可以解释RASSF 7升高与肿瘤发生的关系。Cell Death and Differentiation（2011）18，645-655; doi：10.1038/cdd.2010.137; 2010年11月19日在线发表
Members of the Ras-association domain family (RASSF) of proteins influence apoptosis and cell cycling but little is known about the mechanisms. Here, we show that RASSF7 interacts with N-Ras and mitogen-activated protein kinase kinase 7 (MKK7) to negatively regulate c-Jun N-terminal kinase (JNK) signaling. Stress-induced JNK activation and apoptosis were markedly enhanced in cells depleted of RASSF7 or N-Ras by RNAi knockdown. An interaction with RASSF7 promoted the phosphorylated state of MKK7 but inhibited this kinase's ability to activate JNK. RASSF7 required its RA domain for both interaction with GTP-bound N-Ras and the anti-apoptotic response to stress stimuli. Following prolonged stress, however, RASSF7's antiapoptotic effect was eliminated because of degradation of RASSF7 protein via the ubiquitin-proteasome pathway. Our results indicate that RASSF7 acts in concert with N-Ras to constitute a stress-sensitive temporary mechanism of apoptotic regulation. With initial stress, RASSF7/N-Ras promotes cell survival by inhibiting the MKK7/JNK pathway. However, with prolonged stress, RASSF7 protein undergoes degradation that allows cell death signaling to proceed. Our findings may account for the association of elevated RASSF7 with tumorigenesis. Cell Death and Differentiation (2011) 18, 645-655; doi:10.1038/cdd.2010.137; published online 19 November 2010