Sun Dan, Buttitta Laura
University of Michigan, Department of Molecular, Cellular and Developmental Biology, Ann Arbor, MI 48109, USA.
University of Michigan, Department of Molecular, Cellular and Developmental Biology, Ann Arbor, MI 48109, USA
Development. 2015 Sep 1;142(17):3033-45. doi: 10.1242/dev.120824. Epub 2015 Aug 7.
Protein phosphatase type 2A complex (PP2A) has been known as a tumor suppressor for over two decades, but it remains unclear exactly how it suppresses tumor growth. Here, we provide data indicating a novel role for PP2A in promoting the transition to quiescence upon terminal differentiation in vivo. Using Drosophila eyes and wings as a model, we find that compromising PP2A activity during the final cell cycle prior to a developmentally controlled cell cycle exit leads to extra cell divisions and delays entry into quiescence. By systematically testing the regulatory subunits of Drosophila PP2A, we find that the B56 family member widerborst (wdb) is required for the role of PP2A in promoting the transition to quiescence. Cells in differentiating tissues with compromised PP2A retain high Cdk2 activity when they should be quiescent, and genetic epistasis tests demonstrate that ectopic Cyclin E/Cdk2 activity is responsible for the extra cell cycles caused by PP2A inhibition. The loss of wdb/PP2A function cooperates with aberrantly high Cyclin E protein levels, allowing cells to bypass a robust G0 late in development. This provides an example of how loss of PP2A can cooperate with oncogenic mutations in cancer. We propose that the PP2A complex plays a novel role in differentiating tissues to promote developmentally controlled quiescence through the regulation of Cyclin E/Cdk2 activity.
二十多年来,2A型蛋白磷酸酶复合物(PP2A)一直被认为是一种肿瘤抑制因子,但目前仍不清楚它究竟是如何抑制肿瘤生长的。在此,我们提供的数据表明,PP2A在体内终末分化过程中促进细胞进入静止期方面具有新的作用。以果蝇的眼睛和翅膀为模型,我们发现,在发育控制的细胞周期退出之前的最后一个细胞周期中,破坏PP2A的活性会导致额外的细胞分裂,并延迟进入静止期。通过系统地测试果蝇PP2A的调节亚基,我们发现B56家族成员widerborst(wdb)是PP2A促进向静止期转变作用所必需的。在应该进入静止期时,PP2A功能受损的分化组织中的细胞仍保持较高的Cdk2活性,遗传上位性测试表明,异位的细胞周期蛋白E/Cdk2活性是由PP2A抑制引起的额外细胞周期的原因。wdb/PP2A功能的丧失与异常高的细胞周期蛋白E蛋白水平协同作用,使细胞能够在发育后期绕过强大的G0期。这提供了一个PP2A缺失如何与癌症中的致癌突变协同作用的例子。我们提出,PP2A复合物在分化组织中通过调节细胞周期蛋白E/Cdk2活性,在促进发育控制的静止期方面发挥新的作用。