Ramaswamy S, Nakamura N, Vazquez F, Batt D B, Perera S, Roberts T M, Sellers W R
Department of Adult Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2110-5. doi: 10.1073/pnas.96.5.2110.
PTEN/MMAC1 is a tumor suppressor gene located on chromosome 10q23. Inherited PTEN/MMAC1 mutations are associated with a cancer predisposition syndrome known as Cowden's disease. Somatic mutation of PTEN has been found in a number of malignancies, including glioblastoma, melanoma, and carcinoma of the prostate and endometrium. The protein product (PTEN) encodes a dual-specificity protein phosphatase and in addition can dephosphorylate certain lipid substrates. Herein, we show that PTEN protein induces a G1 block when reconstituted in PTEN-null cells. A PTEN mutant associated with Cowden's disease (PTEN;G129E) has protein phosphatase activity yet is defective in dephosphorylating inositol 1,3,4,5-tetrakisphosphate in vitro and fails to arrest cells in G1. These data suggest a link between induction of a cell-cycle block by PTEN and its ability to dephosphorylate, in vivo, phosphatidylinositol 3,4,5-trisphosphate. In keeping with this notion, PTEN can inhibit the phosphatidylinositol 3,4, 5-trisphosphate-dependent Akt kinase, a downstream target of phosphatidylinositol 3-kinase, and constitutively active, but not wild-type, Akt overrides a PTEN G1 arrest. Finally, tumor cells lacking PTEN contain high levels of activated Akt, suggesting that PTEN is necessary for the appropriate regulation of the phosphatidylinositol 3-kinase/Akt pathway.
PTEN/MMAC1是一种位于10号染色体q23区域的肿瘤抑制基因。PTEN/MMAC1的遗传性突变与一种称为考登病的癌症易感综合征相关。在包括胶质母细胞瘤、黑色素瘤以及前列腺癌和子宫内膜癌在内的多种恶性肿瘤中均发现了PTEN的体细胞突变。其蛋白质产物（PTEN）编码一种双特异性蛋白磷酸酶，此外还能使某些脂质底物去磷酸化。在此，我们表明，当在PTEN缺失的细胞中重组时，PTEN蛋白会诱导G1期阻滞。一种与考登病相关的PTEN突变体（PTEN;G129E）具有蛋白磷酸酶活性，但在体外使肌醇1,3,4,5-四磷酸去磷酸化存在缺陷，并且无法使细胞停滞在G1期。这些数据表明PTEN诱导细胞周期阻滞与其在体内使磷脂酰肌醇3,4,5-三磷酸去磷酸化的能力之间存在联系。与此观点一致的是，PTEN可以抑制磷脂酰肌醇3,4,5-三磷酸依赖性的Akt激酶，后者是磷脂酰肌醇3-激酶的下游靶点，持续激活的Akt（而非野生型Akt）会消除PTEN诱导的G1期阻滞。最后，缺乏PTEN的肿瘤细胞含有高水平的活化Akt，这表明PTEN对于磷脂酰肌醇3-激酶/Akt信号通路的适当调控是必需的。
