PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy
PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy
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DOI：
10.1074/jbc.m108302200
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发表时间：
2002-02-15
影响因子：
4.8
通讯作者：
Donner, DB
中科院分区：
文献类型：
--
作者：
Mayo, LD;Dixon, JE;Donner, DB
PTEN肿瘤抑制蛋白抑制磷脂酰肌醇。3-激酶(PI3K)/Akt信号通路促进Mdm2易位进入细胞核。当被限制在细胞质中时，Mdm2被降解。PTEN抑制Mdm2进入细胞核的能力增加了p53肿瘤抑制蛋白的细胞含量和反活化。逆转录病毒将PTEN转导到U87MG （PTEN null）胶质母细胞瘤细胞中，可增加p53活性和p53靶基因的表达，并诱导细胞周期阻滞。U87MG/PTEN胶质母细胞瘤细胞比U87MG/PTEN零细胞对乙托苷（一种诱导DNA损伤的化疗药物）诱导的死亡更敏感。以前，肿瘤抑制蛋白被认为是单独作用来抑制癌症。我们的研究结果建立了两种主要肿瘤抑制因子活性之间的直接联系，并表明它们共同作用以应对压力和恶性肿瘤。PTEN保护p53免受生存信号的影响，允许p53作为基因组的守护者发挥作用。凭借其保护p53的能力，PTEN可以使肿瘤细胞对依赖p53活性的化疗敏感。p53诱导PTEN基因表达，这里显示PTEN保护p53，表明一个正反馈回路可能会放大细胞对应激、损伤和癌症的反应。
The PTEN tumor suppressor protein inhibits phosphatidylinositol. 3-kinase (PI3K)/Akt signaling that promotes translocation of Mdm2 into the nucleus. When restricted to the cytoplasm, Mdm2 is degraded. The ability of PTEN to inhibit the nuclear entry of Mdm2 increases the cellular content and transactivation of the p53 tumor suppressor protein. Retroviral transduction of PTEN into U87MG (PTEN null) glioblastoma cells increases p53 activity and expression of p53 target genes and induces cell cycle arrest. U87MG/PTEN glioblastoma cells are more sensitive than U87MG/PTEN null cells to death induced by etoposide, a chemotherapeutic agent that induces DNA damage. Previously, tumor suppressor proteins have been supposed to act individually to suppress cancers. Our results establish a direct connection between the activities of two major tumor suppressors and show that they act together to respond to stresses and malignancies. PTEN protects p53 from survival signals, permitting p53 to function as a guardian of the genome. By virtue of its capacity to protect p53, PTEN can sensitize tumor cells to chemotherapy that relies on p53 activity. p53 induces PTEN gene expression, and here it is shown that PTEN protects p53, indicating that a positive feedback loop may amplify the cellular response to stress, damage, and cancer.