Role and mechanism of action of p62/Sqstm1 in Ras-induced tumorigenesis in lung

项目总结/摘要 肺癌是美国主要的癌症相关死亡原因。目前的治疗方法不会导致 治愈大多数患有这种肿瘤的患者。有针对性的抗肿瘤治疗可能会证明更多 有效，但它们的发展将需要更好地了解所涉及的信号级联。Ras 癌基因在人类癌症中经常发生突变，它们在癌症中发挥着毫无疑问的重要作用。 疾病的发生和发展。在肺腺癌中，Ras突变至少存在于 25%的病例，这表明Ras相关信号通路的组分是有希望的候选者， 肺癌治疗的治疗靶点。 Ras致癌转化激活NF-B，NF-B是细胞存活的关键调节因子， 肿瘤进展的介质。非典型PKCs（aPKCs）和它们的衔接子p62与对照组有牵连。 NF-B激活的可能性。最近的研究结果表明，NF-B通路的遗传失活可能 预防或促进肿瘤的发展，这取决于靶器官和炎症是否 答案是参与。然而，NF-B失活在肺肿瘤中的作用尚未被证实。 记录在案。初步研究表明Ras可重复产生肺腺瘤， 在小鼠肺癌的诱导模型中，p62是这些Ras诱导的腺癌所必需的。 肺肿瘤有证据表明，这是一种细胞自主效应，因为p62的缺失严重影响了细胞的功能。 削弱Ras转化永生胚胎成纤维细胞的能力。另外，Ras转化诱导p62 蛋白质通过一种尚未确定的机制积累。这些重要的观察结果有力地表明， p62是Ras诱导的肺肿瘤发生和细胞转化所必需的。 这个项目的长期目标是确定新的信号分子，可以治疗 肺癌的靶点。本提案的总体目标是严格检验以下假设： p62/aPKC/NF-B通路在Ras诱导的肿瘤转化中起关键作用，特别是在肺癌中。这将 通过评估这些重要的信号介质的作用和作用机制， Ras诱导的转化的调节。为实现这一目标而设计的具体目标是：1）测试 p62通过aPKC在体内调节Ras诱导的肺癌的假设; 2）检验以下假设： IKK <$或IKK <$是Ras诱导的肺肿瘤形成的关键介质; 3）阐明细胞和 p62/aPKC/ NF-B通路在Ras诱导转化中的分子机制及其与细胞凋亡的关系 人类肺癌这项工作将增加我们对参与调节的机制的理解， 肺癌，并在长期将提供必要的知识，为发展新的，更多的 特异性，因此毒性较小，治疗这种类型的肿瘤。

Project Summary/Abstract Lung cancer is the leading cancer-related cause of death in the United States. Current treatments do not lead to a cure for most patients with this type of neoplasia. Targeted anti-tumor therapies are likely to prove more effective, but their development will require a better understanding of the signaling cascades involved. Ras oncogenes are frequently mutated in human cancers where they play an unquestionably important role in the genesis and progression of the disease. In lung adenocarcinomas, mutations in Ras are present in at least 25% of cases, suggesting that the components of Ras-related signaling pathways are promising candidates for therapeutic targets in lung cancer treatment. Ras oncogenic transformation activates NF-¿B, a critical regulator of cell survival and an essential mediator of tumor progression. The atypical PKCs (aPKCs) and their adapter p62 are implicated in the control of NF-¿B activation. Recent results demonstrate that genetic inactivation of the NF-¿B pathway may either prevent or promote tumor development, depending on the target organ and whether or not the inflammatory response is involved. However, the effect of NF-¿B inactivation in lung neoplasia has not yet been documented. Preliminary studies demonstrate that Ras reproducibly produces lung adenomas and adenocarcinomas in an inducible model of lung cancer in mice, and that p62 is required for these Ras-induced lung tumors. The evidence suggests that this is a cell-autonomous effect in that the absence of p62 severely impairs the ability of Ras to transform immortal embryo fibroblasts. In addition, Ras transformation induces p62 protein accumulation through a yet-to-be-defined mechanism. These important observations strongly indicate that p62 is necessary for Ras-induced lung tumorigenesis and cell transformation. The long-term goal of this project is to define novel signaling molecules that could be therapeutic targets in lung cancer. The overall objective of this proposal is to rigorously test the hypothesis that the p62/aPKC/NF-¿B pathway is critical in Ras-induced tumor transformation, specifically in lung cancer. This will be achieved by assessing the roles and mechanism of action of these important signaling mediators in the regulation of Ras-induced transformation. The specific aims designed to achieve this are to 1) Test the hypothesis that p62 regulates Ras-induced lung cancer in vivo through the aPKCs; 2) Test the hypothesis that IKK¿ or IKK¿ are critical mediators of Ras-induced formation of lung tumors; 3) Elucidate the cellular and molecular mechanisms of the p62/aPKC/ NF-¿B pathway in Ras-induced transformation and its relevance in human lung cancer. This work will increase our understanding of the mechanisms involved in the regulation of lung cancer, and in the long term will provide the knowledge necessary for the development of novel, more specific, and thus less toxic, therapies for this type of neoplasia.