Suppression of tumorigenesis by the p53 target PUMA
Suppression of tumorigenesis by the p53 target PUMA
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DOI：
10.1073/pnas.0403286101
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发表时间：
2004-06-22
影响因子：
11.1
通讯作者：
Lowe, SW
中科院分区：
文献类型：
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作者：
Hemann, MT;Zilfou, JT;Lowe, SW
p53肿瘤抑制因子调节多种抗增殖过程，使得获得p53突变的细胞具有受损的细胞周期检查点、衰老、凋亡和基因组稳定性。在这里，我们使用稳定的RNA干扰，以检查p53靶基因和Bcl 2家族的促凋亡成员，在p53介导的肿瘤抑制中的作用。siRNA短发夹RNA（shRNA）有效地抑制siRNA的表达和p53依赖的凋亡，但不损害p53的非凋亡功能。与p53 shRNAs相似，p53 shRNAs通过E1 A/ras癌基因组合促进原代鼠成纤维细胞的致癌转化，并显著加速myc-包含的淋巴瘤发生，而不破坏p53依赖的细胞周期停滞。然而，与p53 shRNAs相比，p53 shRNAs在转化中不能与致癌ras协同作用，因此p53 shRNAs执行p53肿瘤抑制功能的能力是可变的。这些结果表明，参与肿瘤抑制的p53效应子功能是上下文依赖性的，并且在某些情况下，严重依赖于单个促凋亡效应子的表达。此外，他们证明了RNA干扰在体内评估推定的肿瘤抑制基因的效用。
The p53 tumor suppressor regulates diverse antiproliferative processes such that cells acquiring p53 mutations have impaired cell-cycle checkpoints, senescence, apoptosis, and genomic stability. Here, we use stable RNA interference to examine the role of PUMA, a p53 target gene and proapoptotic member of the Bcl2 family, in p53-mediated tumor suppression. PUMA short hairpin RNAs (shRNAs) efficiently suppressed PUMA expression and p53-dependent apoptosis but did not impair nonapoptotic functions of p53. Like p53 shRNAs, PUMA shRNAs promoted oncogenic transformation of primary murine fibroblasts by the E1A/ras oncogene combination and dramatically accelerated myc-incluced lymphomagenesis without disrupting p53-dependent cell-cycle arrest. However, the ability of PUMA to execute p53 tumor suppressor functions was variable because, in contrast to p53 shRNAs, PUMA shRNAs were unable to cooperate with oncogenic ras in transformation. These results demonstrate that the p53 effector functions involved in tumor suppression are context dependent and, in some settings, depend heavily on the expression of a single proapoptotic effector. Additionally, they demonstrate the utility of RNA interference for evaluating putative tumor suppressor genes in vivo.