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Tumor-suppressor Fbxw7 targets SIK2 for degradation to interfere with TORC2-AKT signaling in pancreatic cancer.
Cell Biology International ( IF 3.9 ) Pub Date : 2020-05-21 , DOI: 10.1002/cbin.11396
Ming-Xia Zhang 1, 2 , Hao Wang 2 , Guo-Ping Sun 1
Affiliation  

The tumor suppressor F‐box/WD repeat‐containing protein 7 (Fbxw7) is a substrate‐recognition subunit of a ubiquitin ligase complex. We have previously proposed that Fbxw7 inhibited pancreatic cancer cell proliferation and invasion by targeting β‐catenin. To identify other targets of Fbxw7 involved in pancreatic carcinogenesis, we screened the human protein database for Fbxw7 target candidates using the conserved Fbxw7‐recognizing sequences. Twenty‐three candidates are identified, including five known Fbxw7 targets and two cancer‐related genes (salt inducible kinase 2 [SIK2] and ZMIZ1). We identified SIK2 as an Fbxw7 target for degradation by binding to the “TPPPS” motif of SIK2 in pancreatic cancer cells. We also demonstrated that SIK2 promoted proliferation and mitotic progression of pancreatic cancer cells. Moreover, endogenous Fbxw7 downregulates SIK2 protein level for controlling cell cycle progression, possibly by interfering the SIK2/TORC2/AKT signaling pathway to modulate p21 expression. Collectively, these data demonstrate that Fbxw7 targets the cell cycle controller, SIK2, for degradation, thereby leading to the disruption of downstream TORC2/AKT signaling to inhibit pancreatic cancer cell proliferation and cell cycle progression.

中文翻译:

肿瘤抑制因子Fbxw7靶向SIK2进行降解,以干扰胰腺癌中的TORC2-AKT信号传导。

肿瘤抑制因子F-box / WD重复蛋白7(Fbxw7)是泛素连接酶复合物的底物识别亚基。我们先前曾提出,Fbxw7通过靶向β-catenin抑制胰腺癌细胞的增殖和侵袭。为了确定参与胰腺癌发生的Fbxw7的其他靶标,我们使用保守的Fbxw7识别序列筛选了人类蛋白质数据库中的Fbxw7候选靶标。确定了23个候选基因,包括五个已知的Fbxw7靶标和两个与癌症相关的基因(盐诱导型激酶2 [SIK2]和ZMIZ1)。通过与胰腺癌细胞中SIK2的“ TPPPS”基序结合,我们确定SIK2为降解的Fbxw7目标。我们还证明了SIK2可以促进胰腺癌细胞的增殖和有丝分裂进程。此外,p21表达。总体而言,这些数据表明Fbxw7靶向细胞周期控制器SIK2进行降解,从而导致下游TORC2 / AKT信号转导受阻,从而抑制了胰腺癌细胞的增殖和细胞周期的进程。
更新日期:2020-05-21
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