Department of Biochemistry, University of California, Riverside, CA 92521.
Mol Cancer Res. 2013 Sep;11(9):995-1003. doi: 10.1158/1541-7786.MCR-12-0633. Epub 2013 May 30.
The hetero-trimeric PP2A serine/threonine phosphatases containing the regulatory subunit B56, and in particular B56γ, can function as tumor suppressors. In response to DNA damage, the B56γ subunit complexes with the PP2A AC core (B56γ-PP2A) and binds p53. This event promotes PP2A-mediated dephosphorylation of p53 at Thr55, which induces expression of p21, and the subsequent inhibition of cell proliferation and transformation. In addition to dephosphorylation of p53, B56γ-PP2A also inhibits cell proliferation and transformation by a second, as yet unknown, p53-independent mechanism. Here, we interrogated a panel of B56γ mutations found in human cancer samples and cell lines and showed that these mutations lost B56γ tumor-suppressive activity by two distinct mechanisms: one is by disrupting interactions with the PP2A AC core and the other with B56γ-PP2A substrates (p53 and unknown proteins). For the first mechanism, due to the absence of the C catalytic subunit in the complex, the mutants are unable to mediate dephosphorylation of any substrate and thus failed to promote both the p53-dependent and -independent tumor-suppressive functions of B56γ-PP2A. For the second mechanism, the mutants lacked specific substrate interactions and thus partially lost tumor-suppressive function, i.e., either the p53-dependent or p53-independent contingent upon which substrate binding was affected. Overall, these data provide new insight into the mechanisms of tumor suppression by B56γ.
This study further indicates the importance of B56γ-PP2A in tumorigenesis.
包含调节亚基 B56γ 的异三聚体 PP2A 丝氨酸/苏氨酸磷酸酶，特别是 B56γ，可作为肿瘤抑制因子发挥作用。在 DNA 损伤后，B56γ 亚基与 PP2A AC 核心（B56γ-PP2A）结合并与 p53 结合。这一事件促进了 PP2A 介导的 p53 在 Thr55 上的去磷酸化，从而诱导 p21 的表达，随后抑制细胞增殖和转化。除了 p53 的去磷酸化之外，B56γ-PP2A 还通过第二种、迄今为止未知的 p53 非依赖性机制抑制细胞增殖和转化。在这里，我们研究了在人类癌症样本和细胞系中发现的一组 B56γ 突变，并表明这些突变通过两种不同的机制失去了 B56γ 的肿瘤抑制活性：一种是通过破坏与 PP2A AC 核心的相互作用，另一种是与 B56γ-PP2A 底物（p53 和未知蛋白）的相互作用。对于第一种机制，由于复合物中缺乏 C 催化亚基，突变体无法介导任何底物的去磷酸化，因此未能促进 B56γ-PP2A 的 p53 依赖性和非依赖性肿瘤抑制功能。对于第二种机制，突变体缺乏特定的底物相互作用，因此部分丧失了肿瘤抑制功能，即依赖于哪种底物结合受到影响，要么是 p53 依赖性，要么是 p53 非依赖性。总体而言，这些数据为 B56γ 抑制肿瘤的机制提供了新的见解。
本研究进一步表明了 B56γ-PP2A 在肿瘤发生中的重要性。
