Zhu X, Kwon C H, Schlosshauer P W, Ellenson L H, Baker S J
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
Cancer Res. 2001 Jun 1;61(11):4569-75.
Inactivating mutations in the PTEN tumor suppressor gene occur in approximately 30-50% of endometrial carcinomas. PTEN is a phosphatase that negatively regulates the phosphoinositide 3-kinase signaling pathway, including the downstream effector AKT. To evaluate the role of PTEN in endometrial growth regulation, we expressed wild-type or mutant PTEN in endometrial carcinoma cell lines. As expected, expression of exogenous PTEN decreased levels of activated AKT in all cell lines examined. However, PTEN induced a G(1) cell cycle arrest specifically in endometrial carcinoma cells that lack endogenous wild-type PTEN. Growth of cells containing wild-type PTEN was unaffected by exogenous PTEN expression. Growth arrest required a functional phosphatase domain but not the PDZ interaction motif of PTEN. Overall levels of CIP/KIP and INK4 family members, the known inhibitory regulators of the G(1) phase of the cell cycle, were unchanged. However, PTEN induced a specific reduction of cyclin D3 levels and an associated increase in the amount of the inhibitor p27(KIP1) complexed with CDK2. Enforced expression of cyclin D3 abrogated the PTEN-induced cell cycle arrest. Although PTEN signaling directly regulates p27(KIP1) levels in some settings, in endometrial carcinoma cells, PTEN expression indirectly regulated p27(KIP1) activity by modulating levels of cyclin D3. These data support multiple mechanisms of PTEN-induced cell cycle arrest.
PTEN肿瘤抑制基因的失活突变约发生在30%-50%的子宫内膜癌中。PTEN是一种磷酸酶，对磷酸肌醇3激酶信号通路起负调控作用，该通路包括下游效应分子AKT。为评估PTEN在子宫内膜生长调节中的作用，我们在子宫内膜癌细胞系中表达野生型或突变型PTEN。正如预期的那样，外源性PTEN的表达降低了所有检测细胞系中活化型AKT的水平。然而，PTEN特异性地诱导缺乏内源性野生型PTEN的子宫内膜癌细胞出现G1期细胞周期停滞。含有野生型PTEN的细胞生长不受外源性PTEN表达的影响。细胞周期停滞需要一个功能性的磷酸酶结构域，但不需要PTEN的PDZ相互作用基序。细胞周期蛋白依赖性激酶抑制蛋白（CIP/KIP）和INK4家族成员（已知的细胞周期G1期抑制性调节因子）的总体水平没有变化。然而，PTEN导致细胞周期蛋白D3水平特异性降低，同时与细胞周期蛋白依赖性激酶2（CDK2）结合的抑制剂p27KIP1的量相应增加。强制表达细胞周期蛋白D3可消除PTEN诱导的细胞周期停滞。尽管在某些情况下PTEN信号直接调节p27KIP1的水平，但在子宫内膜癌细胞中，PTEN表达通过调节细胞周期蛋白D3的水平间接调节p27KIP1的活性。这些数据支持PTEN诱导细胞周期停滞的多种机制。
