Cell Survival and Cancer

描述（由申请人提供）：这个多学科计划的重点是分子 癌蛋白、酪氨酸激酶受体和肿瘤抑制基因调节细胞存活的机制。该计划有四个项目。研究人员打算研究：i）BCR/ABL表达细胞和BCR/ABL依赖性白血病发生中MDM 2水平升高的机制和意义，BCR/ABL抑制C/EBPalpha表达的机制以及恢复BCR/ABL细胞中C/EBPalpha表达的生物学后果; ii）IGF-1受体促进IRS-1在细胞核中定位的机制，IGF-1 R和STAT-3对IRS-1表达和启动子活性的调节，以及IRS-1、Id 2、pRb和STAT-3在IGF-1介导的细胞凋亡、增殖和分化调节中的作用; iii）通过Fhit基因参与肿瘤抑制的促凋亡作用和Fhit功能丧失在肿瘤发生中的作用; iv）新鉴定的线粒体丝氨酸蛋白酶Omi在半胱天冬酶依赖性和半胱天冬酶非依赖性细胞凋亡中的作用以及ER定位的GSPT-1蛋白参与ER应激诱导的细胞凋亡。 该计划项目的长期目标是利用这些信息作为设计更合理的抗癌治疗方法的分子基础。

DESCRIPTION (provided by applicant): This multidisciplinary program focuses on the molecular mechanisms whereby oncoproteins, tyrosine kinase receptors and tumor suppressor genes regulate cell survival. The program has four projects. There is also a request for an administrative and a nucleic acids core component.The investigators intend to study: i) the mechanisms and the significance of enhanced MDM2 levels in BCR/ABL-expressing cells and BCR/ABL-dependent leukemogenesis, the mechanisms whereby BCR/ABL suppresses C/EBPalpha expression and the biological consequences of restoring C/EBPalpha expression in BCR/ABL cells; ii) the mechanisms whereby the IGF-1 receptor promotes the localization of IRS-1 in the nucleus, the regulation of IRS-1 expression and promoter activity by IGF-1R and STAT-3, and the role of IRS-1, Id2, pRb, and STAT-3 in IGF-1-mediated regulation of apoptosis, proliferation and differentiation; iii) the pro-apoptotic effects involved in tumor suppression by the Fhit gene and the role of Fhit loss of function in tumorigenesis; iv) the role of the newly identified mitochondrial serine proteinase, Omi, in caspase-dependent and caspase-independent apoptosis and the involvement of the ER-localized GSPT-1 protein in the ER stress-induced apoptosis. The long-term objective of this Program Project is to utilize this information as a molecular basis for devising more rational approaches to anti-cancer therapies.