Liang Jiyong, Zubovitz Judit, Petrocelli Teresa, Kotchetkov Rouslan, Connor Michael K, Han Kathy, Lee Jin-Hwa, Ciarallo Sandra, Catzavelos Charles, Beniston Richard, Franssen Edmee, Slingerland Joyce M
Molecular and Cell Biology, Sunnybrook and Women's College Health Sciences Centre, St. Mary's Hospital, McGill University, Montreal, Quebec.
Nat Med. 2002 Oct;8(10):1153-60. doi: 10.1038/nm761. Epub 2002 Sep 16.
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)(PKB(DD)), 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.
在癌症细胞和正常细胞中，有丝分裂原和生长抑制细胞因子信号传导与细胞周期之间的联系机制尚未完全阐明。在此，我们表明蛋白激酶B（PKB）/Akt的激活，部分通过损害p27的核输入和作用，导致对抗增殖信号的抵抗和乳腺癌进展。Akt转染导致细胞质中p27积累，并对细胞因子介导的G1期阻滞产生抗性。p27的核定位信号在苏氨酸157处含有一个Akt共有位点，Akt介导的p27磷酸化在体外损害其核输入。Akt使野生型p27磷酸化，但不使p27T157A磷酸化。在转染组成型活性Akt（T308D S473D）（PKB（DD））的细胞中，p27WT错误定位于细胞质，但p27T157A位于细胞核。在Akt激活的细胞中，p27WT未能引起G1期阻滞，而p27T157A的抗增殖作用未受损。在41%（128例中的52例）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，我们展示了一种新机制，即Akt损害p27功能，这与人类乳腺癌的侵袭性表型相关。
