The prolyl isomerase Pin1 interacts with and downregulates the activity of AMPK leading to induction of tumorigenicity of hepatocarcinoma cells
The prolyl isomerase Pin1 interacts with and downregulates the activity of AMPK leading to induction of tumorigenicity of hepatocarcinoma cells
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DOI：
10.1002/mc.21920
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发表时间：
2013-10
影响因子：
4.6
通讯作者：
P. Khanal;Garam Kim;H. Yun;Hae‐Guk Cho;H. Choi
中科院分区：
文献类型：
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作者：
P. Khanal;Garam Kim;H. Yun;Hae‐Guk Cho;H. Choi
Pin1是一种独特的调节因子，它催化靶蛋白中特定的磷酸丝氨酸/苏氨酸-Pro基序的转化。在此，我们确定AMP激活的蛋白激酶(AMPK)是一种Pin1结合蛋白。与AMPK相关的Pin1野生型，而不是丝氨酸16(S16A)的Pin1突变体。相反，AMPK的结构性活性形式(AMPK-CA)与Pin1野生型相互作用，而不是AMPK的显性阴性形式(AMPK-DN)。此外，AMPK的Ser176位点突变导致AMPK与Pin1的结合显著丧失。去除MEFS中Pin1基因可增强AICAR诱导的AMPK磷酸化。在Pin1、−/−MEF和SK-HEP-1细胞中过表达Pin1可抑制表皮生长因子诱导的AMPK磷酸化，而siRNA下调Pin1基因可增强其磷酸化。PIN1和AMPK的结合被EGF增强，导致它们与蛋白磷酸酶-2A(PP2A)相互作用。此外，Pin1还能增强EGF诱导的PP2A活性。此外，AMPK-WT和AMPK-CA对EGF诱导的JB6-Cl41细胞转化和SK-Hep-1细胞致瘤性均有抑制作用，而AMPK-DN无此作用。在JB6 Cl41细胞和SK-Hep-1细胞中过表达Pin1分别减弱了AMPK对EGF诱导的JB6 Cl41细胞转化和SK-Hep-1细胞致瘤性的抑制作用。综上所述，这些结果表明Pin1通过下调肝癌细胞AMPK活性而在EGF诱导的癌变过程中发挥关键作用。©2012 Wiley期刊，Inc.
Pin1 is a unique regulator that catalyzes the conversion of a specific phospho‐Ser/Thr‐Pro‐containing motif in target proteins. Herein, we identified AMP‐activated protein kinase (AMPK) as a Pin1‐binding protein. Pin1 wild‐type, but not Pin1 mutant at serine 16 (S16A), associated with AMPK. Reciprocally, the constitutively active form of AMPK (AMPK‐CA), but not the dominant negative form of AMPK (AMPK‐DN), interacted with Pin1 wild type. In addition, mutation of Ser176 site in AMPK led to a significant loss of binding between AMPK and Pin1. Ablation of the Pin1 gene in MEFs enhanced AMPK phosphorylation induced by AICAR. Pin1 overexpression in Pin1−/− MEFs and SK‐HEP‐1 cells attenuated AMPK phosphorylation induced by EGF, whereas gene knockdown of Pin1 by siRNA enhanced it. The association between Pin1 and AMPK was increased by EGF, leading to their interaction with protein phosphatase‐2A (PP2A). Furthermore, Pin1 increased the PP2A activity induced by EGF. In addition, AMPK‐WT and AMPK‐CA, but not AMPK‐DN, inhibited EGF‐induced neoplastic cell transformation of JB6 Cl41 cells and tumorigenicity of SK‐HEP‐1 cells. The overexpression of Pin1 in JB6 Cl41 cells and SK‐HEP‐1 cells attenuated the inhibitory effect of AMPK in EGF‐induced neoplastic cell transformation of JB6 Cl41 and tumorigenicity of SK‐HEP‐1 cells, respectively. Taken together, these results indicate that Pin1 plays a pivotal role in EGF‐induced carcinogenesis through downregulation of AMPK activity in hepatocarcinoma cells. © 2012 Wiley Periodicals, Inc.