From the Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
J Biol Chem. 2014 Feb 7;289(6):3217-30. doi: 10.1074/jbc.M113.508515. Epub 2013 Dec 16.
The tumor suppressor PTEN plays a critical role in the regulation of multiple cellular processes that include survival, cell cycle, proliferation, and apoptosis. PTEN is frequently mutated or deleted in various human cancer cells to promote tumorigenesis. PTEN is regulated by SUMOylation, but the SUMO E3 ligase involved in the SUMOylation of PTEN remains unclear. Here, we demonstrated that PIASxα is a SUMO E3 ligase for PTEN. PIASxα physically interacted with PTEN both in vitro and in vivo. Their interaction depended on the integrity of phosphatase and C2 domains of PTEN and the region of PIASxα comprising residues 134-347. PIASxα enhanced PTEN protein stability by reducing PTEN ubiquitination, whereas the mutation of PTEN SUMO1 conjugation sites neutralized the effect of PIASxα on PTEN protein half-life. Functionally, PIASxα, as a potential tumor suppressor, negatively regulated the PI3K-Akt pathway through stabilizing PTEN protein. Overexpression of PIASxα led to G0/G1 cell cycle arrest, thus triggering cell proliferation inhibition and tumor suppression, whereas PIASxα knockdown or deficiency in catalytic activity abolished the inhibition. Together our studies suggest that PIASxα is a novel SUMO E3 ligase for PTEN, and it positively regulates PTEN protein level in tumor suppression.
肿瘤抑制因子 PTEN 在调节多种细胞过程中发挥着关键作用，包括存活、细胞周期、增殖和凋亡。PTEN 在各种人类癌细胞中经常发生突变或缺失，以促进肿瘤发生。PTEN 的表达受到 SUMOylation 的调控，但参与 PTEN SUMOylation 的 SUMO E3 连接酶尚不清楚。在这里，我们证明了 PIASxα 是 PTEN 的 SUMO E3 连接酶。PIASxα 在体外和体内均与 PTEN 发生物理相互作用。它们的相互作用依赖于 PTEN 的磷酸酶和 C2 结构域以及 PIASxα 的残基 134-347 区域的完整性。PIASxα 通过减少 PTEN 的泛素化来增强 PTEN 蛋白稳定性，而 PTEN SUMO1 缀合位点的突变则中和了 PIASxα 对 PTEN 蛋白半衰期的影响。功能上，PIASxα 作为一种潜在的肿瘤抑制因子，通过稳定 PTEN 蛋白负调控 PI3K-Akt 通路。PIASxα 的过表达导致 G0/G1 细胞周期停滞，从而触发细胞增殖抑制和肿瘤抑制，而 PIASxα 的敲低或催化活性缺失则消除了这种抑制作用。综上所述，我们的研究表明 PIASxα 是 PTEN 的一种新型 SUMO E3 连接酶，它在肿瘤抑制中正向调节 PTEN 蛋白水平。
