PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest
PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest
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DOI：
10.1038/nm761
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发表时间：
2002-10-01
期刊：
影响因子：
82.9
通讯作者：
Slingerland, JM
中科院分区：
文献类型：
--
作者：
Liang, J;Zubovitz, J;Slingerland, JM
在癌症或正常细胞中，连接促有丝分裂和生长抑制细胞因子信号传导和细胞周期的机制尚未完全阐明。在这里，我们表明，蛋白激酶B（PKB）/Akt的激活有助于抵抗抗增殖信号和乳腺癌的进展，部分通过损害核进口和p27的作用。Akt转染引起细胞质p27积累和对精氨酸介导的G1期阻滞的抗性。p27的核定位信号在苏氨酸157处包含Akt共有位点，Akt对p27的磷酸化在体外损害了其核输入。Akt磷酸化野生型p27，而不是p27 T157 A。在组成型活性Akt（T308 DS 473 D）（PKBDD）转染的细胞中，p27 WT错误定位于细胞质，但p27 T157 A位于细胞核。在Akt活化的细胞中，p27 WT不能引起G1期阻滞，而p27 T157 A的抗增殖作用没有受损。在41%（52/128）的原发性人类乳腺癌中观察到细胞质p27与Akt激活相关，并与患者预后不良相关。因此，我们显示了一种新的机制，Akt损害p27的功能，这是与人类乳腺癌的侵袭性表型。
Mechanisms linking mitogenic and growth inhibitory cytokine signaling and the cell cycle have not been fully elucidated in either cancer or in normal cells. Here we show that activation of protein kinase B (PKB)/Akt contributes to resistance to antiproliferative signals and breast cancer progression in part by impairing the nuclear import and action of p27. Akt transfection caused cytoplasmic p27 accumulation and resistance to cytokine-mediated G1 arrest. The nuclear localization signal of p27 contains an Akt consensus site at threonine 157, and p27 phosphorylation by Akt impaired its nuclear import in vitro. Akt phosphorylated wild-type p27 but not p27T157A. In cells transfected with constitutively active Akt(T308DS473D) (PKBDD), p27WT mislocalized to the cytoplasm, but p27T157A was nuclear. In cells with activated Akt, p27WT failed to cause G1 arrest, while the antiproliferative effect of p27T157A was not impaired. Cytoplasmic p27 was seen in 41% (52 of 128) of primary human breast cancers in conjunction with Akt activation and was correlated with a poor patient prognosis. Thus, we show a novel mechanism whereby Akt impairs p27 function that is associated with an aggressive phenotype in human breast cancer.