Ren Cong, Zhang Jin, Yan Wensheng, Zhang Yanhong, Chen Xinbin
From the Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of California, Davis, California 95616.
From the Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of California, Davis, California 95616
J Biol Chem. 2016 Apr 29;291(18):9629-37. doi: 10.1074/jbc.M115.712125. Epub 2016 Feb 23.
TAp73, a member of the p53 family tumor suppressors, plays a critical rule in tumor suppression and neuronal development. However, how p73 activity is controlled at the posttranscriptional level is not well understood. Here, we showed that TAp73 activity is regulated by RNA-binding protein PCBP2. Specifically, we found that knockdown or knock-out of PCBP2 reduces, whereas ectopic expression of PCBP2 increases, TAp73 expression. We also showed that PCBP2 is necessary for p73 mRNA stability via the CU-rich elements in p73 3'-UTR. To uncover the biological relevance of PCBP2-regulated TAp73 expression, we showed that ectopic expression of PCBP2 inhibits, whereas knockdown or knock-out of PCBP2 increases, the production of reactive oxygen species (ROS) in a TAp73-dependent manner. Additionally, we found that glutaminase 2 (GLS2), a modulator of p73-dependent antioxidant defense, is also involved in PCBP2-regulated ROS production. Moreover, we generated PCBP2-deficient mice and primary mouse embryonic fibroblasts (MEFs) and showed that loss of PCBP2 leads to decreased p73 expression and, subsequently, increased ROS production and accelerated cellular senescence. Together, our data suggest that PCBP2 regulates p73 expression via mRNA stability and p73-dependent biological function in ROS production and cellular senescence.
TAp73是p53家族肿瘤抑制因子的成员之一，在肿瘤抑制和神经元发育中发挥关键作用。然而，p73活性在转录后水平是如何被调控的，目前还不太清楚。在此，我们表明TAp73的活性受RNA结合蛋白PCBP2的调控。具体而言，我们发现敲低或敲除PCBP2会降低TAp73的表达，而PCBP2的异位表达则会增加TAp73的表达。我们还表明，PCBP2通过p73 3'-UTR中富含CU的元件对p73 mRNA稳定性是必需的。为了揭示PCBP2调控TAp73表达的生物学意义，我们表明PCBP2的异位表达会抑制，而敲低或敲除PCBP2则会以TAp73依赖的方式增加活性氧（ROS）的产生。此外，我们发现谷氨酰胺酶2（GLS2）作为p73依赖的抗氧化防御的调节因子，也参与了PCBP2调控的ROS产生。而且，我们构建了PCBP2缺陷型小鼠和原代小鼠胚胎成纤维细胞（MEF），并表明PCBP2的缺失会导致p73表达降低，随后增加ROS产生并加速细胞衰老。总之，我们的数据表明PCBP2通过mRNA稳定性以及在ROS产生和细胞衰老中p73依赖的生物学功能来调控p73的表达。
