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首页> 外文期刊>Cell biology international. >Generation of a tissue-specific transgenic model for K8 phosphomutants: A tool to investigate the role of K8 phosphorylation during skin carcinogenesis in vivo
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Generation of a tissue-specific transgenic model for K8 phosphomutants: A tool to investigate the role of K8 phosphorylation during skin carcinogenesis in vivo

机译：为K8膦仿生组织特异性转基因模型：一种探讨K8磷酸化在体内皮肤致癌过程中的作用的工具

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摘要

Keratin 8/18, the predominant keratin pair of simple epithelia, is known to be aberrantly expressed in several squamous cell carcinomas (SCCs), where its expression is often correlated with increased invasion, neoplastic progression, and poor prognosis. The majority of keratin 8/18 structural and regulatory functions are governed by posttranslational modifications, particularly phosphorylation. Apart from filament reorganization, cellular processes including cell cycle, cell growth, cellular stress, and apoptosis are known to be orchestrated by K8 phosphorylation at specific residues in the head and tail domains. Even though deregulation of K8 phosphorylation at two significant sites (Serine(73)/Serine(431)) has been implicated in neoplastic progression of SCCs by various in vitro studies, including ours, it is reported to be highly context-dependent. Therefore, to delineate the precise role of Kereatin 8 phosphorylation in cancer initiation and progression, we have developed the tissue-specific transgenic mouse model expressing Keratin 8 wild type and phosphodead mutants under Keratin 14 promoter. Subjecting these mice to 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate-mediated skin carcinogenesis revealed that Keratin 8 phosphorylation may lead to an early onset of tumors compared to Keratin 8 wild-type expressing mice. Conclusively, the transgenic mouse model developed in the present study ascertained a positive impact of Keratin 8 phosphorylation on the neoplastic transformation of skin-squamous cells.
机译：角蛋白8/18是简单上皮的主要角蛋白对，已知在几种鳞状细胞癌（SCC）中异常表达，其表达通常与侵袭性增加、肿瘤进展和预后不良相关。大多数角蛋白8/18的结构和调节功能由翻译后修饰，尤其是磷酸化控制。除了丝重组外，包括细胞周期、细胞生长、细胞应激和凋亡在内的细胞过程已知是由头部和尾部结构域中特定残基的K8磷酸化协调的。尽管通过各种体外研究（包括我们的研究），在两个重要位点（丝氨酸（73）/丝氨酸（431））解除K8磷酸化的调节与SCC的肿瘤进展有关，但据报道其高度依赖于上下文。因此，为了阐明Kereatin 8磷酸化在癌症发生和发展中的确切作用，我们开发了在角蛋白14启动子下表达角蛋白8野生型和磷酸化死亡突变体的组织特异性转基因小鼠模型。将这些小鼠置于7,12-二甲基苯并（a）蒽/12-O-十四烷基佛波醇-13-醋酸盐介导的皮肤癌变中，发现与角蛋白8野生型表达小鼠相比，角蛋白8磷酸化可能导致肿瘤的早期发病。总之，本研究开发的转基因小鼠模型证实了角蛋白8磷酸化对皮肤鳞状细胞的肿瘤转化有积极影响。

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