Nuclear-cytoplasmic partitioning of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) differentially regulates the cell cycle and apoptosis
Nuclear-cytoplasmic partitioning of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) differentially regulates the cell cycle and apoptosis
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DOI：
10.1158/0008-5472.can-05-1888
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发表时间：
2005-09-15
期刊：
影响因子：
11.2
通讯作者：
Eng, C
中科院分区：
文献类型：
--
作者：
Chung, JH;Eng, C
10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）是一种使蛋白质和脂质底物脱磷酸化的肿瘤抑制磷酸酶，在遗传性和散发性乳腺癌中都发现了突变。已显示细胞PTEN调节Akt磷酸化、促分裂原活化蛋白激酶（MAPK）磷酸化、p27（kip 1）和细胞周期蛋白D I蛋白水平。此外，我们和其他人已经表明，PTEN不仅可以调节细胞周期，而且还可以调节细胞凋亡。直到最近，PTEN的功能一直被认为是通过细胞质PTEN发生的。然而，我们已经表明，PTEN定位于细胞核，并且这种定位与细胞周期的GO-G相一致。此外，我们已经表明，PTEN具有二分核定位序列（NLS）样序列，所需的主要穹窿蛋白介导的核输入。这些研究结果表明，亚细胞定位的PTEN可能会调节其功能，核定位的PTEN可能会调节独特的细胞功能，已归因于细胞质的PTEN。为了检验这种可能性，我们使用稳定转染有两种不同的NLS突变体PTEN构建体（其不定位于细胞核）的MCF-7 Tet-Off乳腺癌细胞系分析下游PTEN读数，并将这些与转染有野生型PTEN和空载体对照细胞的细胞进行比较。我们发现，细胞质中的PTEN下调Akt的磷酸化和上调p27（kip 1），而核中的PTEN下调cyclin D1和阻止MAPK的磷酸化。此外，我们观察到细胞周期阻滞需要细胞核中的PTEN，我们发现细胞质中的PTEN是细胞凋亡所需的。我们的观察结果表明，核质分区差异调节细胞周期和凋亡，并以这种方式，提供进一步的证据表明，核进口的PTEN应发挥作用，在致癌作用。
Phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a tumor suppressor phosphatase that dephosphorylates both protein and lipid substrates, is found to be mutated in both heritable and sporadic breast cancer. Cellular PTEN has been shown to regulate Akt phosphorylation, mitogen-activated protein kinase (MAPK) phosphorylation, p27(kip1), and cyclin D I protein levels. Additionally, we and others have shown that PTEN can regulate not only the cell cycle but also cellular apoptosis. Until recently, the functions of PTEN have been thought to occur through cytoplasmic PTEN. However, we have shown that PTEN localizes to the nucleus and that this localization coincides with the GO-G, phases of the cell cycle. Furthermore, we have shown that PTEN has bipartite nuclear localization sequence (NLS)-like sequences that are required for major vault protein-mediated nuclear import. These findings suggest that subcellular localization of PTEN may regulate its function and that nuclear-localized PTEN may regulate unique cellular functions that have been attributed to cytoplasmic PTEN. To examine this possibility, we analyzed downstream PTEN readouts using MCF-7 Tet-Off breast cancer cell lines stably transfected with two different NLS mutant PTEN constructs, which do not localize to the nucleus, and compared these with cells transfected with wild-type PTEN and empty vector control cells. We found that cytoplasmic PTEN downregulates phosphorylation of Akt and up-regulates p27(kip1), whereas nuclear PTEN down-regulates cyclin D1 and prevents the phosphorylation of MAPK. Additionally, whereas we observe that nuclear PTEN is required for cell cycle arrest, we found that cytoplasmic PTEN is required for apoptosis. Our observations show that nuclear-cytoplasmic partitioning differentially regulates the cell cycle and apoptosis and, in this manner, provide further evidence that nuclear import of PTEN should play a role in carcinogenesis.