Regulation of JNK-signaling molecules by the gep oncogenes

描述（由申请人提供）：卵巢癌被确定为美国癌症死亡的第五大原因，每年约有16,000人死亡。尽管在了解这种疾病的病理方面取得了重大进展，但仍有52%的患者死于这些癌症的侵袭性生长。最近有研究发现，脂质生长因子溶血磷脂酸（LPA）促进卵巢癌的发生和发展。我们最近的研究表明，lpa介导的致癌信号涉及gep癌基因，由G？12和G？13，不同的调控MAP激酶，包括Jun n -末端激酶（JNK）。反过来，这些mapk引发了不同生理刺激所需的多种细胞反应。G？12/13表明可能涉及一种可以调节特定信号反应的支架蛋白。最近我们已经证明，在LPA刺激下，这些gep致癌基因与参与JNKs激活的支架蛋白相互作用（Kashef et al., 2005）。这种新型支架蛋白被称为JNK相互作用亮氨酸拉链蛋白（JLP），可以通过g12 /13增强JNK的激活。此外，我们的研究表明，JLP还能拴住？-PIX，一种Rac/ cdc42特异性鸟嘌呤核苷酸交换因子12/13通过它可以激活jnk模块。基于这些结果，我们假设G？12/13-JLP相互作用与G？12/13介导的多种细胞反应的激活。在本申请中，我们提出在以下具体目标下检验这一假设：目标1:G - 13-JLP-？-PIX通过定点诱变相互作用；目的2:G？13、JLP和？-PIX形成信号复合体；目的3：确定JLP在G？12/13和目标4：定义JLP- G的作用？12/13信号在卵巢癌发生和发展中的作用除了表征卵巢癌进展的病因因素外，这些研究的结果有望确定治疗该疾病的新治疗靶点。

DESCRIPTION (provided by applicant): Ovarian cancer is identified as the fifth leading cause of cancer death in the United States with approximately 16,000 deaths every year. Although major advances have been made in understanding the pathology of this disease, 52 % of patients die because of the aggressive growth of these cancers. It has been recently observed that the lipid growth factor lysophosphatidic acid (LPA) promotes ovarian cancer genesis and progression. Our recent studies have shown that LPA-mediated oncogenic signaling involves the gep oncogenes, defined by the activated mutants of G?12 and G?13, that differentially regulate a number of MAP kinases including Jun N-terminal kinase (JNK). These MAPKs, in turn, elicit a multitude of cellular responses required for different physiological stimuli. The signaling complexity and precision of G?12/13 indicates the possible involvement of a scaffolding protein that can modulate specific signaling responses. Recently we have shown that these gep oncogenes, upon stimulation with LPA, interact with a scaffolding protein involved in the activation of JNKs (Kashef et al., 2005). This novel scaffolding protein known as JNK-interacting Leucine- zipper Protein (JLP) potentiates the activation of JNK by G?12/13. In addition, our studies indicate that JLP also tethers ?-PIX, a Rac/CDC42-specific guanine nucleotide exchange factor, to G?12/13 through which the JNK-module can be activated. Based on these results, we hypothesize that G?12/13-JLP interaction is critically involved in G?12/13-mediated activation of diverse cellular responses. In this application, we propose to test this hypothesis under the following specific aims: Aim 1: Characterization of G?13-JLP-?-PIX interaction through site-directed mutagenesis; Aim 2: Analysis of the interrelationship of G?13, JLP, and ?-PIX in forming a signaling complex; Aim 3: Defining the role of JLP on the oncogenic activity of G?12/13 and Aim 4: defining the Role of JLP- G?12/13 signaling in ovarian cancer genesis and progression. In addition to characterizing the etiological factors involved in the progression of ovarian cancer, the outcome of these studies is expected to identify novel therapeutic targets for the treatment of the disease.