Regulation of JNK-signaling molecules by the gep oncogenes

描述(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。虽然在了解这种疾病的病理方面取得了重大进展，但52%的患者死于这些癌症的侵袭性生长。最近发现，脂类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，该基因由激活的G？12和G？13突变体定义，对包括Jun N-末端激酶(JNK)在内的多个MAP激酶进行差异调节。这些MAPK反过来又引发了不同生理刺激所需的大量细胞反应。G？12/13的信号复杂性和精确度表明，可能有一种支架蛋白参与调节特定的信号反应。最近，我们已经证明，当LPA刺激时，这些gep癌基因与参与JNK激活的支架蛋白相互作用(Kashef等人，2005年)。这种新的支架蛋白被称为JNK相互作用亮氨酸拉链蛋白(JLP)，它可以通过G？12/13增强JNK的激活。此外，我们的研究表明，JLP还将RAC/Cdc42特异性的鸟嘌呤核苷酸交换因子？-PIX拴在G？12/13上，通过它可以激活JNK-模块。根据这些结果，我们推测G？12/13-JLP相互作用在G？12/13介导的多种细胞反应的激活中起关键作用。在这一应用中，我们建议在以下特定目标下检验这一假说：目标1：通过定点突变表征G？13-JLP-？-PIX相互作用；目标2：分析G？13、JLP和？-PIX在形成信号复合体中的相互关系；目标3：确定JLP在G？12/13致癌活性中的作用；目标4：确定JLP-G？12/13信号在卵巢癌发生和发展中的作用。除了确定与卵巢癌进展有关的病因，这些研究的结果有望确定治疗该疾病的新靶点。

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.