CDC25B partners with PP2A to induce AMPK activation and tumor suppression in triple negative breast cancer.
CDC25B partners with PP2A to induce AMPK activation and tumor suppression in triple negative breast cancer.
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DOI：
10.1093/narcan/zcaa039
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发表时间：
2020-12
期刊：
影响因子：
5.1
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Cairns J;Ly RC;Niu N;Kalari KR;Carlson EE;Wang L
细胞分裂周期25（CDC 25）双特异性磷酸酶通过激活细胞周期蛋白依赖性激酶/细胞周期蛋白复合物来正向调节细胞周期。在这里，我们证明，除了其在细胞周期调控中的作用，CDC 25 B的功能作为一个调节蛋白磷酸酶2A（PP 2A），一个主要的细胞丝氨酸/苏氨酸磷酸酶，通过其与PP 2A催化亚基的直接相互作用。重要的是，CDC 25 B改变了PP 2A对AMP激活的蛋白激酶信号传导（AMPK）的调节，通过抑制PP 2A使AMPK去磷酸化来增加AMPK活性。CDC 25 B耗竭通过抑制二甲双胍诱导的AMPK活化导致二甲双胍耐药。此外，与单独的CDC 25 B抑制相比，CDC 25 B和PP 2A的双重抑制进一步抑制从乳腺癌的患者来源的异种移植模型分离的3D类器官的生长。我们的研究确定了CDC 25 B作为PP 2A的调节剂，并揭示了控制关键能量代谢标志物AMPK活性的机制。
Cell division cycle 25 (CDC25) dual specificity phosphatases positively regulate the cell cycle by activating cyclin-dependent kinase/cyclin complexes. Here, we demonstrate that in addition to its role in cell cycle regulation, CDC25B functions as a regulator of protein phosphatase 2A (PP2A), a major cellular Ser/Thr phosphatase, through its direct interaction with PP2A catalytic subunit. Importantly, CDC25B alters the regulation of AMP-activated protein kinase signaling (AMPK) by PP2A, increasing AMPK activity by inhibiting PP2A to dephosphorylate AMPK. CDC25B depletion leads to metformin resistance by inhibiting metformin-induced AMPK activation. Furthermore, dual inhibition of CDC25B and PP2A further inhibits growth of 3D organoids isolated from patient derived xenograft model of breast cancer compared to CDC25B inhibition alone. Our study identifies CDC25B as a regulator of PP2A, and uncovers a mechanism of controlling the activity of a key energy metabolism marker, AMPK.
cdc25A 和 cdc25B 蛋白在甲状腺肿瘤中的表达。
影响因子：
8.8
作者：
Ito, Y;Yoshida, H;Nakano, K;Kobayashi, K;Yokozawa, T;Hirai, K;Matsuzuka, F;Matsuura, N;Kakudo, K;Kuma, K;Miyauchi, A
通讯作者：
Miyauchi, A