MRK SUPPRESSION OF APOPTOSIS IN CANCER

MRK 抑制癌症细胞凋亡

• 批准号: 6335929
• 负责人: ROSAMARIA RUGGIERI
• 金额: $ 6.21万
• 依托单位: PICOWER INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-03 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6335929
• 关键词: BCL2 gene /protein; antineoplastics; apoptosis; biological signal transduction; cell line; cysteine endopeptidases; enzyme activity; gene mutation; interleukin 3; intermolecular interaction; mitochondria; neoplasm /cancer chemotherapy; phosphoproteins; phosphorylation; protein kinase

Tumors result from an imbalance between cell proliferation and cell death. In addition to mutations that affect cell proliferation, tumors select for genetic alterations that inhibit apoptosis or programmed cell death, especially in later stages of tumor progression. Thus, most malignant tumors acquire an increased threshold for apoptosis that contributes to tumor size and to the resistance of tumor cells to treatment. Despite our increased understanding of the mechanisms that control apoptosis, very little is known about the signals that suppress apoptosis in tumor cells. We have identified a new intracellular signaling molecule, MRK (MLK and MEKK related kinase), and found that it contributes to the suppression of apoptosis. We showed that a kinase inactive MRK interferes with the ability of oncogenic H- rasV12 to transform cells and that an active form of MRK protects IL-3 dependent cells from cell death induced by survival factor removal. In addition, we have established that MRK interacts with HAX-1, an integral membrane protein localized largely to mitochondria and bearing significant homology with the Bcl-2 family of proteins that are known to regulate apoptosis. Our general hypothesis is that abnormal cell survival mechanisms are important determinants of tumor growth and that by interfering with deregulated survival signals, one might increase the susceptibility of tumors to apoptosis and thus improve cancer therapy. The focus of the current proposal is to test the hypothesis that the novel kinase MRK mediates cell survival signals that contribute to the suppression of apoptosis in cancer. Studies in Aim 1 will elucidate the role of abnormal MRK activity in the suppression of apoptosis in cancer cells challenged with chemotherapeutic agents. Studies in Aim 2 will characterize the interaction between MRK and its binding partner HAX-1, and determine the role of this interaction in the MRK anti-apoptotic function. Studies in Aim 3 will address the mechanism of suppression of cell death by MRK by testing its effect on the regulation of known pro-apoptotic proteins, such as BAD and caspase 9. Our long-term objectives are to elucidate the signal transduction pathway mediated by MRK and to understand the mechanisms that contribute to the increased resistance of cancer cells to induction of apoptosis.

肿瘤是由细胞增殖和细胞死亡之间的不平衡引起的。 除了影响细胞增殖的突变之外，肿瘤还选择抑制细胞凋亡或程序性细胞死亡的遗传改变，特别是在肿瘤进展的后期阶段。 因此，大多数恶性肿瘤获得增加的细胞凋亡阈值，这有助于肿瘤大小和肿瘤细胞对治疗的抗性。 尽管我们对控制细胞凋亡的机制有了更多的了解，但对抑制肿瘤细胞凋亡的信号知之甚少。 我们发现了一种新的细胞内信号分子MRK（MLK and MEKK related kinase），并发现它有助于抑制细胞凋亡。 我们发现，激酶失活的MRK干扰致癌H-rasV 12转化细胞的能力，并且MRK的活性形式保护IL-3依赖性细胞免于由存活因子去除诱导的细胞死亡。 此外，我们已经确定MRK与HAX-1相互作用，HAX-1是一种主要定位于线粒体的完整膜蛋白，与已知调节细胞凋亡的Bcl-2蛋白家族具有显著的同源性。 我们的一般假设是，异常的细胞存活机制是肿瘤生长的重要决定因素，通过干扰失调的存活信号，可能会增加肿瘤对凋亡的易感性，从而改善癌症治疗。 目前的建议的重点是测试的假设，新激酶MRK介导的细胞存活信号，有助于抑制细胞凋亡的癌症。 目的1中的研究将阐明异常MRK活性在用化疗剂攻击的癌细胞中抑制细胞凋亡中的作用。 目标2中的研究将表征MRK及其结合伴侣HAX-1之间的相互作用，并确定这种相互作用在MRK抗凋亡功能中的作用。 目标3中的研究将通过测试MRK对已知促凋亡蛋白（如BAD和半胱天冬酶9）的调节作用来解决MRK抑制细胞死亡的机制。 我们的长期目标是阐明由MRK介导的信号转导途径，并了解有助于癌细胞对诱导凋亡的抗性增加的机制。