Interaction with Pyruvate Kinase M2 Destabilizes Tristetraprolin by Proteasome Degradation and Regulates Cell Proliferation in Breast Cancer.
Interaction with Pyruvate Kinase M2 Destabilizes Tristetraprolin by Proteasome Degradation and Regulates Cell Proliferation in Breast Cancer.
复制标题
与丙酮酸激酶 M2 的相互作用通过蛋白酶体降解破坏 Tristetraprolin 的稳定性并调节乳腺癌中的细胞增殖。
DOI：
10.1038/srep22449
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发表时间：
2016-03-01
影响因子：
4.6
通讯作者：
Huang G
中科院分区：
文献类型：
--
作者：
Huang L;Yu Z;Zhang Z;Ma W;Song S;Huang G
丙酮酸激酶M2 （PKM2）在大多数癌症中主要表达，在Warburg效应中起关键作用。然而，PKM2作为肿瘤支持蛋白的作用机制尚未完全阐明。在这里，我们发现tristeprolin （TTP）是PKM2的一个新的结合伙伴，它是一种富含au的元件结合蛋白，调节mRNA的稳定性。我们的数据显示，PKM2通过促进TTP的磷酸化、泛素化和蛋白酶体降解，降低其mRNA的转换能力，最终损害乳腺癌细胞的活力，从而抑制TTP蛋白水平。p38/丝裂原活化蛋白激酶（MAPK）途径可能参与pkm2介导的TTP降解，而p38抑制剂或siRNA处理可消除pkm2诱导的TTP蛋白降解。这些发现表明PKM2-TTP关联对于调节乳腺癌细胞增殖至关重要，因此是癌症的潜在治疗靶点。
Pyruvate kinase M2 (PKM2), which is predominantly expressed in most cancers, plays a key role in the Warburg effect. However, how PKM2 functions as a tumor supportive protein has not been fully elucidated. Here, we identified tristetraprolin (TTP), an AU-rich, element-binding protein that regulates mRNA stability, as a new binding partner of PKM2. Our data reveal that PKM2 suppresses TTP protein levels by promoting its phosphorylation, ubiquitination, and proteasome degradation, reducing its mRNA turnover ability and ultimately impairing cell viability in breast cancer cells. The p38/mitogen-activated protein kinase (MAPK) pathway might be involved in PKM2-mediated TTP degradation, while treatment with the p38 inhibitor or siRNA abolished PKM2-induced TTP protein degradation. These findings demonstrate that PKM2–TTP association is crucial for regulating breast cancer cell proliferation and is therefore a potential therapeutic target in cancer.