The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region
The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region
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DOI：
10.1073/pnas.96.18.10182
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发表时间：
1999-08-31
影响因子：
11.1
通讯作者：
Hanafusa, H
中科院分区：
文献类型：
--
作者：
Georgescu, MM;Kirsch, KH;Hanafusa, H
PTEN是最近发现的一种肿瘤抑制因子，在胶质母细胞瘤、子宫内膜癌和前列腺癌等多种癌症中失活。含有氨基末端磷酸酶结构域，作为磷脂酰肌醇3，4，5-三磷酸酶拮抗磷脂酰肌醇3-OH激酶的活性。PTEN还含有羧基末端结构域，我们讨论了该区域的作用，类似于氨基末端磷酸酶结构域，是肿瘤中鉴定的许多突变的靶点。羧基末端突变体在PTEN缺陷的胶质母细胞瘤细胞中的表达允许细胞的锚定非依赖性生长，否则会被野生型PTEN抑制。这些突变体在细胞中的稳定性由于快速降解而降低。虽然羧基末端区域含有调节PEST序列和PDZ结合基序，但这些特异性元件不具有肿瘤抑制功能。对影响PTEN稳定性的羧基末端点突变的研究表明，这些突变位于强烈预测的β链中。令人惊讶的是，这些突变体的磷酸酶活性的影响与这些结构元件的破坏程度相关。我们的结论是，羧基末端区域是必不可少的调节PTEN的稳定性和酶活性，在这个区域的突变是负责肿瘤抑制表型的逆转。我们还提出，这些突变引起的分子构象变化构成了PTEN失活的机制。
PTEN is a recently identified tumor suppressor inactivated in a variety of cancers such as glioblastoma and endometrial and prostate carcinoma. It contains an amino-terminal phosphatase domain and acts as a phosphatidylinositol 3,4,5-trisphosphate phosphatase antagonizing the activity of the phosphatidylinositol 3-OH kinase. PTEN also contains a carboxyl-terminal domain, and we addressed the role of this region that, analogous to the amino-terminal phosphatase domain, is the target of many mutations identified in tumors. Expression of carboxyl-terminal mutants in PTEN-deficient glioblastoma cells permitted the anchorage-independent growth of the cells that otherwise was suppressed by wild-type PTEN. The stability of these mutants in cells was reduced because of rapid degradation. Although the carboxyl-terminal region contains regulatory PEST sequences and a PDZ-binding motif, these specific elements were dispensable for the tumor-suppressor function. The study of carboxyl-terminal point mutations affecting the stability of PTEN revealed that these were located in strongly predicted beta-strands. Surprisingly, the phosphatase activity of these mutants was affected in correlation with the degree of disruption of these structural elements. We conclude that the carboxyl-terminal region is essential for regulating PTEN stability and enzymatic activity and that mutations in this region are responsible for the reversion of the tumor-suppressor phenotype. We also propose that the molecular conformational changes induced by these mutations constitute the mechanism for PTEN inactivation.