6-Phosphofructo-2-kinase (PFKFB3) promotes cell cycle progression and suppresses apoptosis via Cdk1-mediated phosphorylation of p27.
6-Phosphofructo-2-kinase (PFKFB3) promotes cell cycle progression and suppresses apoptosis via Cdk1-mediated phosphorylation of p27.
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DOI：
10.1038/cddis.2014.292
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发表时间：
2014-07-17
影响因子：
9
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葡萄糖代谢的控制和细胞周期必须协调，以保证在细胞周期的不同阶段有足够的ATP和合成代谢底物。6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶家族（PFKFB1-4）是通过合成果糖-2,6-二磷酸（F2,6BP）来调节葡萄糖代谢的，果糖-2,6-二磷酸是6-磷酸果糖-1激酶（Pfk-1）的有效变构激活剂。PFKFB3在人类癌症中过表达，受HIF-1α、Akt和PTEN的调控，是多种癌症类型生存和生长所必需的。虽然大多数关于PFKFB3在癌症进展中作用的功能研究都引用了它在糖酵解调节中的公认功能，但最近的观察发现，PFKFB3也可以运输到细胞核，其产物F2,6BP激活细胞周期蛋白依赖性激酶（Cdks）。特别是，F2,6BP刺激cdk介导的Cip/Kip蛋白p27（苏氨酸187）的磷酸化，进而导致p27的泛素化和蛋白酶体降解。由于p27是G1/S转变的有效抑制因子和细胞凋亡的激活因子，我们假设已知PFKFB3对细胞周期进程和预防细胞凋亡的需求可能部分归因于F2,6BP激活Cdks的能力。在这项研究中，我们证明siRNA沉默内源性PFKFB3抑制Cdk1活性，从而稳定p27蛋白水平，导致细胞周期阻滞在G1/S，增加HeLa细胞的凋亡。重要的是，我们证明了siRNA沉默PFKFB3表达导致的凋亡增加和G1/S转变的抑制被p27的siRNA沉默逆转。结合先前的出版物，这些观察结果支持一个模型，即PFKFB3和F2,6BP不仅作为Pfk-1的调节剂，而且作为Cdk1活性的调节剂，因此在转化细胞中将葡萄糖代谢与细胞增殖和存活结合起来。
The control of glucose metabolism and the cell cycle must be coordinated in order to guarantee sufficient ATP and anabolic substrates at distinct phases of the cell cycle. The family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) are well established regulators of glucose metabolism via their synthesis of fructose-2,6-bisphosphate (F2,6BP), a potent allosteric activator of 6-phosphofructo-1-kinase (Pfk-1). PFKFB3 is overexpressed in human cancers, regulated by HIF-1α, Akt and PTEN, and required for the survival and growth of multiple cancer types. Although most functional studies of the role of PFKFB3 in cancer progression have invoked its well-recognized function in the regulation of glycolysis, recent observations have established that PFKFB3 also traffics to the nucleus and that its product, F2,6BP, activates cyclin-dependent kinases (Cdks). In particular, F2,6BP stimulates the Cdk-mediated phosphorylation of the Cip/Kip protein p27 (threonine 187), which in turn results in p27's ubiquitination and proteasomal degradation. As p27 is a potent suppressor of the G1/S transition and activator of apoptosis, we hypothesized that the known requirement of PFKFB3 for cell cycle progression and prevention of apoptosis may be partly due to the ability of F2,6BP to activate Cdks. In this study, we demonstrate that siRNA silencing of endogenous PFKFB3 inhibits Cdk1 activity, which in turn stabilizes p27 protein levels causing cell cycle arrest at G1/S and increased apoptosis in HeLa cells. Importantly, we demonstrate that the increase in apoptosis and suppression of the G1/S transition caused by siRNA silencing of PFKFB3 expression is reversed by co-siRNA silencing of p27. Taken together with prior publications, these observations support a model whereby PFKFB3 and F2,6BP function not only as regulators of Pfk-1 but also of Cdk1 activity, and therefore serve to couple glucose metabolism with cell proliferation and survival in transformed cells.