Novel Roles of Hakai in Cell Proliferation and Oncogenesis
Novel Roles of Hakai in Cell Proliferation and Oncogenesis
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DOI：
10.1091/mbc.e08-08-0845
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发表时间：
2009-08-01
影响因子：
3.3
通讯作者：
Fujita, Yasuyuki
中科院分区：
文献类型：
--
作者：
Figueroa, Angelica;Kotani, Hirokazu;Fujita, Yasuyuki
在肿瘤发展过程中，细胞因癌蛋白和肿瘤抑制蛋白的错误调节而获得多种表型变化。 Hakai 最初被鉴定为 E-钙粘蛋白复合物的 E3 泛素连接酶，可调节细胞与细胞的接触。在这里，我们提供的证据表明 Hakai 在各种细胞过程和肿瘤发生中发挥着至关重要的作用。 Hakai 的过度表达不仅影响细胞间接触，而且影响上皮细胞和成纤维细胞的增殖。此外，Hakai 的敲低显着抑制了转化上皮细胞的增殖。 Hakai 的表达与人体组织的增殖率相关，并且在人结肠癌和胃腺癌中高度上调。此外，我们还发现 PTB 相关剪接因子 (PSF)（一种 RNA 结合蛋白）是一种新型 Hakai 相互作用蛋白。通过使用 cDNA 阵列，我们确定了各种特定的 PSF 相关 mRNA，编码参与多种癌症相关过程的蛋白质。 Hakai 影响 PSF 结合这些 mRNA 的能力，并且 PSF 短发夹 RNA 或显性失活 PSF 突变体的表达显着抑制 Hakai 过表达细胞的增殖。总的来说，这些结果表明 Hakai 是细胞增殖的重要调节因子，并且 Hakai 可能是一种癌蛋白和癌症治疗的潜在分子靶标。
During tumor development, cells acquire multiple phenotypic changes upon misregulation of oncoproteins and tumor suppressor proteins. Hakai was originally identified as an E3 ubiquitin-ligase for the E-cadherin complex that regulates cell-cell contacts. Here, we present evidence that Hakai plays a crucial role in various cellular processes and tumorigenesis. Overexpression of Hakai affects not only cell-cell contacts but also proliferation in both epithelial and fibroblast cells. Furthermore, the knockdown of Hakai significantly suppresses proliferation of transformed epithelial cells. Expression of Hakai is correlated to the proliferation rate in human tissues and is highly up-regulated in human colon and gastric adenocarcinomas. Moreover, we identify PTB-associated splicing factor (PSF), an RNA-binding protein, as a novel Hakai-interacting protein. By using cDNA arrays, we have determined various specific PSF-associated mRNAs encoding proteins that are involved in several cancer-related processes. Hakai affects the ability of PSF to bind these mRNAs, and expression of PSF short hairpin RNA or a dominant-negative PSF mutant significantly suppresses proliferation of Hakai-overexpressing cells. Collectively, these results suggest that Hakai is an important regulator of cell proliferation and that Hakai may be an oncoprotein and a potential molecular target for cancer treatment.