Serine 15 phosphorylation of p53 directs its interaction with B56γ and the tumor suppressor activity of B56γ-specific protein phosphatase 2A
Serine 15 phosphorylation of p53 directs its interaction with B56γ and the tumor suppressor activity of B56γ-specific protein phosphatase 2A
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DOI：
10.1128/mcb.00983-07
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发表时间：
2008-01-01
影响因子：
5.3
通讯作者：
Liu, Xuan
中科院分区：
文献类型：
--
作者：
Shouse, Geoffrey P.;Cai, Xin;Liu, Xuan
较早的研究表明，B56γ特异性蛋白磷酸酶2a（B56γ-PPP2A）和p53肿瘤抑制活性之间的功能联系。在DNA损伤后，形成了包括B56γ-PP2A和p53在内的复合物，从而导致p53的Thr55去磷酸化，p53转录靶标P21的诱导和细胞增殖的抑制。尽管在DNA损伤后观察到p53和B56γ之间的相互作用增强，但尚不清楚基本机制及其在PP2A肿瘤抑制功能中的重要性。在这项研究中，我们表明，DNA损伤后B56伽马和p53之间的相互作用增加需要在Ser15处p53的ATM依赖性磷酸化。此外，我们证明了B56伽马3诱导的细胞增殖抑制作用，g（1）中细胞周期停滞的诱导以及锚固非依赖性生长的阻塞也取决于p53和p53-b56伽马相互作用的Ser15磷酸化。综上所述，我们的结果提供了Ser15磷酸化介导的p53-B56伽马相互作用与PP2A对p53肿瘤抑制活性的调节之间的机械联系。我们还显示了ATM活性与B56γ-PP2A的肿瘤抑制功能之间的重要联系。
Earlier studies have demonstrated a functional link between B56 gamma-specific protein phosphatase 2A (B56 gamma-PP2A) and p53 tumor suppressor activity. Upon DNA damage, a complex including B56 gamma-PP2A and p53 is formed which leads to Thr55 dephosphorylation of p53, induction of the p53 transcriptional target p21, and the inhibition of cell proliferation. Although an enhanced interaction between p53 and B56 gamma is observed after DNA damage, the underlying mechanism and its significance in PP2A tumor-suppressive function remain unclear. In this study, we show that the increased interaction between B56 gamma and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15. In addition, we demonstrate that the B56 gamma 3-induced inhibition of cell proliferation, induction of cell cycle arrest in G(1), and blockage of anchorage-independent growth are also dependent on Ser15 phosphorylation of p53 and p53-B56 gamma interaction. Taken together, our results provide a mechanistic link between Ser15 phosphorylation-mediated p53-B56 gamma interaction and the modulation of p53 tumor suppressor activity by PP2A. We also show an important link between ATM activity and the tumor-suppressive function of B56 gamma-PP2A.