Attenuation of proteolysis-mediated cyclin E regulation by alternatively spliced Parkin in human colorectal cancers
Attenuation of proteolysis-mediated cyclin E regulation by alternatively spliced Parkin in human colorectal cancers
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DOI：
10.1002/ijc.24565
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发表时间：
2009-11-01
影响因子：
6.4
通讯作者：
Chiba, Tsutomu
中科院分区：
文献类型：
--
作者：
Ikeuchi, Kyoko;Marusawa, Hiroyuki;Chiba, Tsutomu
Parkin 作为针对多种底物的 E3 连接酶，在泛素蛋白酶体系统中发挥着关键作用。我们最近发现 Parkin 缺陷小鼠易发生肿瘤，这提供了 Parkin 是肿瘤抑制基因的证据。 Parkin 基因的功能障碍在各种人类癌症中经常观察到，但 Parkin 功能障碍引起的细胞周期破坏导致癌变的机制尚不清楚。在这里，我们证明结肠上皮细胞中的 Parkin 表达以细胞周期相关的方式受到调节。表皮生长因子 (EGF) 刺激上调人类结肠细胞中的 Parkin 基因表达。抑制磷酸肌醇 3-激酶 [PI(3)K]-Akt 依赖性途径可抑制生长因子诱导的 Parkin 表达。在 43 个人类结直肠癌组织中的 18 个（42%）中检测到具有跨越外显子 3-6 的各种缺失的选择性剪接 Parkin 亚型的表达。野生型 Parkin 诱导细胞周期蛋白 E 蛋白降解，但在结肠癌中鉴定的选择性剪接 Parkin 显示细胞周期蛋白 E 蛋白水解缺陷。这些发现表明 Parkin 表达是由生长因子刺激诱导的，并参与结肠细胞的细胞周期调节。选择性剪接 Parkin 亚型的肿瘤特异性表达可能通过减弱人类结直肠癌中蛋白水解介导的细胞周期蛋白 E 调节来增强细胞增殖。 (C)2009年UICC
Parkin has a critical role in the ubiquitin-proteasome system as an E3-ligase targeting several substrates. Our recent finding that Parkin-deficient mice are susceptible to tumorigenesis provided evidence that Parkin is a tumor suppressor gene. Dysfunction of the Parkin gene is frequently observed in various human cancers, but the mechanism underlying the cell cycle disruption induced by Parkin dysfunction that leads to carcinogenesis is not known. Here, we demonstrated that Parkin expression in colonic epithelial cells is regulated in a cell cycle-associated manner. Epidermal growth factor (EGF) stimulation upregulated Parkin gene expression in human colon cells. Inhibition of the phosphoinositide 3-kinase [PI(3)K]-Akt-dependent pathways suppressed growth factor-induced Parkin expression. The expression of alternatively spliced Parkin isoforms with various deletions spanning exons 3-6 was detected in 18 of 43 (42%) human colorectal cancer tissues. Wildtype Parkin induced the degradation of cyclin E protein, but the alternatively spliced Parkin identified in colon cancers showed defective proteolysis of cyclin E. These findings indicate that Parkin expression is induced by growth factor stimulation and is involved in the cell cycle regulation of colon cells. Tumor-specific expression of alternatively spliced Parkin isoforms might contribute to enhanced cell proliferation through the attenuation of proteolysis-mediated cyclin E regulation in human colorectal cancers. (C) 2009 UICC