Regulation of PTEN Activity in Cancer Cells

癌细胞中 PTEN 活性的调节

• 批准号: 6764253
• 负责人: Emmanuelle Joelle Meuillet
• 金额: $ 29.97万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6764253
• 关键词: Drosophilidae; biological signal transduction; genetic regulation; intermolecular interaction; molecular oncology; neoplastic cell; phosphomonoesterases; protein localization; protein protein interaction; protein structure function; protein transport; selenium; thioredoxin; tissue /cell culture; tumor suppressor proteins

DESCRIPTION (provided by applicant): Regulation of PTEN activity and translocation in normal and cancer cells. PTEN (phosphatase and tensin homolog deleted on chromosome ten) is a recently identified tumor suppressor, which is deleted/mutated in human tumors including glioblastomas, carcinomas of the prostate, uterus, bladder and breast and malignant melanomas. PTEN dephosphorylates the 3-position of phosphatidylinositol (Pdtlns)-3-phosphates, thus, preventing activation of Akt by Ptdlns-3-kinase. PTEN also dephosphorylates focal adhesion kinase (p125FAK) and Shc, a SH2-phosphotyrosine-binding adapter protein that links tyrosine kinases to Ras signaling and the MAP kinase pathway. PTEN contains a C2 lipid binding domain at its C-terminal end, which is responsible for its' binding to phosphatidylcholine at the inner leaflet of the plasma membrane in a Ca2+-independent manner. It has been suggested that this domain may influence the activity of the protein, but no clear-cut role for the C2 domain of PTEN has been proposed.We have recently found that a small redox protein, thioredoxin, binds directly to the C2 domain of PTEN and thereby is able to negatively regulate the lipid activity of PTEN. Thioredoxin binds to the Cys212 of PTEN forming a stable complex, which can be regulated in a redox dependent manner. Moreover, the addition of selenium to cells, which is know to increase thioredoxin reductase activity, is able to restore PTEN activity.Hence, the hypotheses upon which our studies are based are that 1) PTEN activity is allosterically regulated by a small redox protein and indirectly by selenium and that 2) PTEN activity can be regulated indirectly by its C2 domain. The objectives of our proposed studies are directed towards a better understanding of the role of the C2 domain in the translocation of PTEN and in the regulation of the activity of PTEN via its interaction with other proteins.

描述（由申请人提供）：正常细胞和癌细胞中 PTEN 活性和易位的调节。 PTEN（十号染色体上删除的磷酸酶和张力蛋白同源物）是最近发现的一种肿瘤抑制基因，在人类肿瘤中被删除/突变，包括胶质母细胞瘤、前列腺癌、子宫癌、膀胱癌和乳腺癌以及恶性黑色素瘤。 PTEN 使磷脂酰肌醇 (Pdtlns)-3-磷酸的 3 位去磷酸化，从而防止 Ptdlns-3-激酶激活 Akt。 PTEN 还可使粘着斑激酶 (p125FAK) 和 Shc 去磷酸化，Shc 是一种 SH2-磷酸酪氨酸结合接头蛋白，可将酪氨酸激酶与 Ras 信号传导和 MAP 激酶通路连接起来。 PTEN 在其 C 末端含有一个 C2 脂质结合结构域，负责以不依赖 Ca2+ 的方式与质膜内叶的磷脂酰胆碱结合。有人认为该结构域可能会影响蛋白质的活性，但尚未提出 PTEN C2 结构域的明确作用。我们最近发现一种小的氧化还原蛋白，硫氧还蛋白，直接与 PTEN 的 C2 结构域结合。 PTEN 从而能够负调节 PTEN 的脂质活性。硫氧还蛋白与 PTEN 的 Cys212 结合形成稳定的复合物，可以以氧化还原依赖性方式进行调节。此外，向细胞中添加硒可以增加硫氧还蛋白还原酶活性，从而能够恢复 PTEN 活性。因此，我们的研究基于的假设是 1) PTEN 活性由一个小的氧化还原蛋白进行变构调节，并且2) PTEN 活性可以通过其 C2 结构域间接调节。我们提出的研究的目的是为了更好地理解 C2 结构域在 PTEN 易位中的作用以及通过其与其他蛋白质的相互作用调节 PTEN 活性的作用。