Phosphorylation-independent stabilization of p27kip1 by the phosphoinositide 3-kinase pathway in glioblastoma cells
Phosphorylation-independent stabilization of p27kip1 by the phosphoinositide 3-kinase pathway in glioblastoma cells
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DOI：
10.1074/jbc.m408348200
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发表时间：
2005-01-21
影响因子：
4.8
通讯作者：
Stokoe, D
中科院分区：
文献类型：
--
作者：
Brandts, CH;Bilanges, B;Stokoe, D
PTEN抑癌基因是体细胞突变的常见靶点，特别是在多形性胶质母细胞瘤和前列腺癌中。PTEN基因突变的胶质母细胞瘤细胞中PTEN的表达导致细胞周期停滞于G(0)/G(1)，这至少部分是通过增加p27(Kip1)水平来实现的。在这里，我们发现p27(Kip1)不受转录调控，但p27kip1蛋白在抑制磷脂酰肌醇(PI)3-激酶途径后表现出更高的稳定性。由于已知p27(Kip1)蛋白的稳定性受磷酸化的调节，我们研究了PI 3-激酶抑制后对磷酸化模式的修饰。生化证据表明，p27kip1在包括Ser-10和Ser-178在内的几个丝氨酸残基上被磷酸化，但这种磷酸化不受PI 3-激酶活性的影响。P27(Kip1)磷酸化位点突变体的诱导表达进一步证实了这一点，表明p27(Kip1)在G(1)/S转变过程中通过PI 3-激酶途径以一种不依赖于磷酸化的方式失稳。
The PTEN tumor suppressor gene is a frequent target of somatic mutation, particularly in glioblastoma multiform and prostate cancer. The expression of PTEN in PTEN-mutant glioblastoma cells leads to a cell cycle arrest in G(0)/G(1) that is mediated at least partially by increased p27(kip1) levels. Here we show that p27(kip1) is not regulated by transcriptional control but that p27kip1 protein shows increased stability after inhibition of the phosphoinositide (PI) 3-kinase pathway. Because p27(kip1) protein stability is known to be regulated by phosphorylation, we have examined modifications in the phosphorylation pattern after PI 3-kinase inhibition. Biochemical evidence suggests that p27kip1 is phosphorylated on several serine residues, including Ser-10 and Ser-178, but that phosphorylation is unaltered by PI 3-kinase activity. This is further confirmed by the inducible expression of p27(kip1) phosphorylation site mutants, suggesting that p27(kip1) is destabilized in a phosphorylation-independent manner by the PI 3-kinase pathway at the G(1)/S transition.