KSR, a Modifier of Ras-Mediated Cell Transformation

描述（由申请方提供）：原癌基因的激活和肿瘤抑制因子的失活驱动体内肿瘤形成和培养细胞的转化。然而，其他有助于致癌信号转导的基因可以改变肿瘤易感性。Ras激酶抑制因子1（KSR 1）是致癌Ras的肿瘤发生和细胞转化的调节因子。这项研究的目的是解释KSR 1作用的分子机制。该实验室的最新数据表明，KSR 1具有Raf/MEK/ERK信号传导盒的分子支架的预期特性。此外，KSR 1的缺失阻止了组成型活性的RasV 12转化培养中的细胞，并显着减少了RasV 12诱导的体内肿瘤形成。新的数据表明，KSR 1与小窝蛋白-1相互作用，以RasV 12诱导的转化和肿瘤发生的关键方式调节Raf/MEK/ERK信号转导盒的亚细胞组装和激活。实验还表明，相关蛋白KSR 2对细胞增殖和代谢具有明显的影响。第三组研究揭示了KSR蛋白与影响其功能的激酶家族的相互作用。这些观察结果表明，以前未确定的，但生理上重要的，通过Raf/MEK/ERK信号盒和调节细胞代谢的机制，有助于肿瘤发生的机制的相互依赖性。该提案将检验KSR蛋白通过依赖和独立于Raf/MEK/ERK激酶级联的机制影响致瘤潜力的假设。这些机制的细节将通过以下方式揭示：1）确定KSR 1在ERK激活和细胞转化的空间调节中的贡献，2）确定KSR 2在调节KSR 1功能和RasV 12肿瘤发生中的作用，以及3）确定能量平衡效应物在调节KSR蛋白和激活的RasV 12中的作用。公共卫生相关性：原癌基因Ras是多种人类癌症的常见突变贡献者。KSR 1在调节Ras的致瘤潜力中起着重要作用。因此，研究KSR蛋白在肿瘤形成中的调节可能为调节癌症易感性的分子机制提供新的见解。

DESCRIPTION (provided by applicant): The activation of proto-oncogenes and the inactivation of tumor suppressors drive tumor formation in vivo and the transformation of cells in culture. However, other genes that contribute to the transduction of oncogenic signals can modify tumor susceptibility. Kinase Suppressor of Ras 1 (KSR1) is a modifier of tumorigenesis and cell transformation by oncogenic Ras. The goal of this research is to explain the molecular mechanisms underlying the action of KSR1. Recent data from this laboratory demonstrate that KSR1 has properties expected of a molecular scaffold for the Raf/MEK/ERK signaling cassette. Furthermore, deletion of KSR1 prevents constitutively active RasV12 from transforming cells in culture and markedly diminishes RasV12-induced tumor formation in vivo. New data demonstrate that KSR1 interacts with caveolin-1 to regulate the subcellular assembly and activation of the Raf/MEK/ERK signaling cassette in a manner critical to RasV12-induced transformation and tumorigenesis. Experiments also demonstrate that the related protein, KSR2, has a distinct effect on cell proliferation and metabolism. A third set of studies reveal the interaction of KSR proteins with a kinase family that affects their function. These observations suggest a previously unidentified, but physiologically important, interdependence of mechanisms contributing to tumorigenesis via the Raf/MEK/ERK signaling cassette and mechanisms regulating cellular metabolism. This proposal will test the hypothesis that KSR proteins affect tumorigenic potential via mechanisms that are dependent and independent of the Raf/MEK/ERK kinase cascade. The details of those mechanisms will be revealed by: 1) determining the contribution of KSR1 in the spatial regulation of ERK activation and cell transformation, 2) determining the role of KSR2 in regulating KSR1 function and RasV12 tumorigenesis, and 3) determining the role of effectors of energy balance in regulating KSR proteins and activated RasV12. PUBLIC HEALTH RELEVANCE: The proto-oncogene Ras is a commonly mutated contributor to multiple human cancers. KSR1 plays a potent role in regulating the tumorigenic potential of Ras. Thus, study of KSR proteins in the regulation of tumor formation is likely to provide novel insights into the molecular mechanisms regulating cancer susceptibility.