Ral GTPase Down-regulation Stabilizes and Reactivates p53 to Inhibit Malignant Transformation
Ral GTPase Down-regulation Stabilizes and Reactivates p53 to Inhibit Malignant Transformation
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DOI：
10.1074/jbc.m114.565796
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发表时间：
2014-11-07
影响因子：
4.8
通讯作者：
Sebti, Said M.
中科院分区：
文献类型：
--
作者：
Tecleab, Awet;Zhang, Xiaolei;Sebti, Said M.
Ral GTP酶是Ras的关键效应子，但它们诱导恶性转化的分子机制还不清楚。在这项研究中，我们发现K-Ras，RalB，有时RalA的表达，而不是AKT 1/2和c-Raf，是维持低水平的p53在人类癌细胞中所需的，这些细胞含有突变型K-Ras和野生型p53。K-Ras、RalB和有时RalA的下调增加p53蛋白水平，并导致p21表达的p53依赖性上调（WAF）。K-Ras、RalA和RalB耗竭增加了p53的稳定性，如共济失调毛细血管扩张症突变的激酶激活、Ser-15磷酸化增加和p53半衰期显著增加（高达6倍）所示。此外，K-Ras和RalB的耗竭抑制锚定非依赖性生长和侵袭，并以p53依赖性方式干扰细胞周期进程。RalA的耗竭以p53依赖性方式抑制侵袭。因此，K-Ras和RalB以及可能的RalA蛋白的表达对于维持低水平的p53是至关重要的，并且这些GTP酶的下调通过显著增强其稳定性来重新激活p53，并且这有助于抑制恶性转化。
Ral GTPases are critical effectors of Ras, yet the molecular mechanism by which they induce malignant transformation is not well understood. In this study, we found the expression of K-Ras, RalB, and sometimes RalA, but not AKT1/2 and c-Raf, to be required for maintaining low levels of p53 in human cancer cells that harbor mutant K-Ras and wild-type p53. Down-regulation of K-Ras, RalB, and sometimes RalA increases p53 protein levels and results in a p53-dependent up-regulation of the expression of p21(WAF). K-Ras, RalA, and RalB depletion increases p53 stability as demonstrated by ataxia telangiectasia-mutated kinase activation, increased Ser-15 phosphorylation, and a significant (up to 6-fold) increase in p53 half-life. Furthermore, depletion of K-Ras and RalB inhibits anchorage-independent growth and invasion and interferes with cell cycle progression in a p53-dependent manner. Depletion of RalA inhibits invasion in a p53-dependent manner. Thus, expression of K-Ras and RalB and possibly RalA proteins is critical for maintaining low levels of p53, and down-regulation of these GTPases reactivates p53 by significantly enhancing its stability, and this contributes to suppression of malignant transformation.