The RASSF3 Candidate Tumor Suppressor Induces Apoptosis and G1-S Cell-Cycle Arrest via p53
The RASSF3 Candidate Tumor Suppressor Induces Apoptosis and G1-S Cell-Cycle Arrest via p53
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DOI：
10.1158/0008-5472.can-12-0572
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发表时间：
2012-06-01
期刊：
影响因子：
11.2
通讯作者：
Hata, Yutaka
中科院分区：
文献类型：
--
作者：
Kudo, Takumi;Ikeda, Mitsunobu;Hata, Yutaka
RASSF 3是RASSF蛋白家族中最小的成员，可作为肿瘤抑制因子发挥作用。与这个重要家族的其他成员不同，RASSF 3抑制肿瘤形成的机制仍然未知。在这里，我们表明，RASSF 3的表达诱导p53依赖性细胞凋亡和它的消耗减弱DNA损伤诱导的细胞凋亡。我们发现RASSF 3诱导的细胞凋亡依赖于p53的表达。RASSF 3 i（n）的外源性表达可导致G（1）-S期阻滞，且这种阻滞也是p53依赖性的。相反，RASSF 3的缺失促进细胞周期进程，消除UVB和VP-16诱导的G（1）-S阻滞，降低p53蛋白和靶基因表达，并阻止DNA修复。RASSF 3显示直接与MDM 2相互作用并促进MDM 2的泛素化，MDM 2是靶向p53降解的E3连接酶，从而增加p53稳定性。总之，我们的研究结果表明RASSF 3的肿瘤抑制活性，这是通过p53稳定和调节细胞凋亡和细胞周期发生的。Cancer Res; 72（11）; 2901-11.（C）2012年AACR。
RASSF3 is the smallest member of the RASSF family of proteins that function as tumor suppressors. Unlike other members of this important family, the mechanisms through which RASSF3 suppresses tumor formation remain unknown. Here, we show that RASSF3 expression induces p53-dependent apoptosis and its depletion attenuates DNA damage-induced apoptosis. We found that RASSF3-induced apoptosis depended upon p53 expression. Exogenous expression of RASSF3 i(n)ducedG(1)-S arrest, which was also p53 dependent. In contrast, loss of RASSF3 promoted cell-cycle progression, abrogated UVB- and VP-16-induced G(1)-S arrest, decreased p53 protein and target gene expression, and prevented DNA repair. RASSF3 was shown to directly interact with and facilitate the ubiquitination of MDM2, the E3 ligase that targets p53 for degradation, thereby increasing p53 stabilization. Together, our findings show the tumor suppressor activity of RASSF3, which occurs through p53 stabilization and regulation of apoptosis and the cell cycle. Cancer Res; 72(11); 2901-11. (C)2012 AACR.