Gottschalk A R, Basila D, Wong M, Dean N M, Brandts C H, Stokoe D, Haas-Kogan D A
Department of Radiation Oncology, University of California at San Francisco, 94143, USA.
Cancer Res. 2001 Mar 1;61(5):2105-11.
The tumor suppressor PTEN is one of the most commonly inactivated genes in human cancer. Glioblastoma multiforme cells harboring mutant PTEN have abnormally high levels of 3' phosphoinositides and elevated protein kinase B activity. Expression of wild-type PTEN in glioma cells, containing endogenous mutant PTEN, reduces 3' phosphoinositides levels, inhibits PKB activity, and induces G1 cell cycle arrest. We investigated the mechanism of the PTEN-induced growth arrest in glioma cell lines. Expression of PTEN is associated with increased expression of p27Kip1, decreased expression of cyclins A and D3, inhibition of cdk2 activity, and dephosphorylation of pRb. Inactivation of p53, by the human papilloma virus E6 oncoprotein, does not prevent PTEN-induced G1 arrest, implying that p53 is not required for G1 arrest. In contrast, p27Kip1 antisense oligonucleotides abrogated the growth arrest induced by PTEN. Furthermore, blocking p27Kip1 expression prevented the PTEN-induced reduction of cyclin-dependent kinase 2 activity, indicating that p27Kip1 functions upstream of cyclin-dependent kinase 2 in the PTEN regulatory cascade. These results implicate p27Kip1 as a critical mediator of PTEN-induced G1 arrest.
肿瘤抑制因子PTEN是人类癌症中最常失活的基因之一。携带突变型PTEN的多形性胶质母细胞瘤细胞具有异常高水平的3'磷酸肌醇和升高的蛋白激酶B活性。在含有内源性突变型PTEN的胶质瘤细胞中表达野生型PTEN，可降低3'磷酸肌醇水平，抑制PKB活性，并诱导G1期细胞周期停滞。我们研究了PTEN诱导胶质瘤细胞系生长停滞的机制。PTEN的表达与p27Kip1表达增加、细胞周期蛋白A和D3表达降低、cdk2活性抑制以及pRb去磷酸化有关。人乳头瘤病毒E6癌蛋白使p53失活，并不阻止PTEN诱导的G1期停滞，这意味着G1期停滞不需要p53。相反，p27Kip1反义寡核苷酸消除了PTEN诱导的生长停滞。此外，阻断p27Kip1表达可防止PTEN诱导的细胞周期蛋白依赖性激酶2活性降低，表明p27Kip1在PTEN调节级联中在细胞周期蛋白依赖性激酶2的上游起作用。这些结果表明p27Kip1是PTEN诱导的G1期停滞的关键介质。
