Polycystin-1 Inhibits Cell Proliferation through Phosphatase PP2A/B56α
Polycystin-1 Inhibits Cell Proliferation through Phosphatase PP2A/B56α
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Polycystin-1 通过磷酸酶 PP2A/B56 α 抑制细胞增殖
DOI：
10.1155/2019/2582401
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发表时间：
2019-09-19
影响因子：
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通讯作者：
Wang, Zuocheng
中科院分区：
文献类型：
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作者：
Tang, Yan;Yang, JungWoo;Wang, Zuocheng
常染色体显性遗传性多囊肾病(ADPKD)与多种细胞缺陷有关，如过度增殖、细胞凋亡和去分化。多囊蛋白-1(PC1)的突变占ADPKD的85%。在这里，我们发现野生型(WT)或突变体PC1(称为PC1-5TMC)由最后五个跨膜(TM)结构域和C末端组成(称为PC1-5TMC)抑制细胞增殖和蛋白质翻译，以及mTOR的下游效应，与以前的报道一致。蛋白磷酸酶2A(PP2A)复合体的亚基B56α被敲除，或应用PP2A抑制剂冈田酸或Calyculin A，均可阻断PC1和PC1-5TMC对细胞增殖的抑制作用，表明PP2A/B56α介导了PC1对细胞增殖的调控。除了磷酸化的S6和4EBP1外，B56α也被PC1和PC1-5TMC下调。此外，B56α的下调可能是由mTOR而不是AKT介导的，这可能是PC1抑制的增殖依赖于PP2A的原因。
Autosomal dominant polycystic kidney disease (ADPKD) is associated with a number of cellular defects such as hyper-proliferation, apoptosis, and dedifferentiation. Mutations in polycystin-1 (PC1) account for similar to 85% of ADPKD. Here, we showed that wild-type (WT) or mutant PC1 composed of the last five transmembrane (TM) domains and the C-terminus (termed PC1-5TMC) inhibits cell proliferation and protein translation, as well as the downstream effectors of mTOR, consistent with previous reports. Knockdown of B56 alpha, a subunit of the protein phosphatase 2A (PP2A) complex, or application of PP2A inhibitor okadaic acid or calyculin A, abolished the inhibitory effect of PC1 and PC1-5TMC on proliferation, indicating that PP2A/B56 alpha mediates the regulation of cell proliferation by PC1. In addition to the phosphorylated S6 and 4EBP1, B56 alpha was also downregulated by PC1 and PC1-5TMC. Furthermore, the downregulation of B56 alpha, which may be mediated by mTOR but not AKT, can account for the dependence of PC1-inhibited proliferation on PP2A.