TRAIL Receptors in Apoptosis and Cancer

肿瘤坏死因子受体(TNFR)家族的死亡受体通过调节细胞程序性死亡或凋亡，在免疫系统的发育和功能中发挥重要作用。本研究拟对新发现的TNFR家族TRAIL受体(DR4、DR5、TRAIL-R3、TRAIL-R4)的信号转导机制进行研究，其在肿瘤细胞敏感性和正常细胞对TRAIL诱导的细胞凋亡抵抗中的作用是由死亡促进受体DR4和DR5与死亡拮抗剂诱骗受体TRAIL-R3和TRAIL-R4之间的平衡控制的。其次，细胞对TRAIL诱导的细胞凋亡的敏感性也受内源性凋亡抑制分子的控制，如Flat(Flip)和抗凋亡的Bcl-2家族成员。第三，DR4和DR5的凋亡信号需要一个不同于FADD/Mort-1的接头分子，通过分析这些受体在不同肿瘤细胞系以及正常组织或细胞中的表达水平，分析这些受体的表达水平，从而在细胞对TRAIL诱导的凋亡的敏感性中发挥作用。最后，建议分析特异性抗凋亡蛋白在调节TRAIL信号通路中的作用，并鉴定和克隆DR4和DR5的相互作用伙伴(S)。这些研究将有助于阐明TRAIL受体的信号转导机制及其生物学功能。这可能为癌症的新治疗方法奠定基础。

Death receptor of the tumor necrosis factor receptor (TNFR) family play fundamental roles in the development and functions of the immune system, by their ability to regulate programmed cell death or apoptosis. In this application it is proposed to stud the mechanism of signal transduction by the newly discovered TRAIL receptors (DR4, DR5, TRAIL-R3, TRAIL- R4) which belong to the TNFR family, and their role in the sensitivity of tumor cells and resistance of normal cells to TRAIL-induced apoptosis is controlled by a balance between the levels of the death promoting receptors, DR4 and DR5, and the death antagonist decoy receptor TRAIL- R3 and TRAIL-R4. Second, sensitivity of cells to TRAIL-induced apopptosis is also controlled by endogenous apoptosis inhibitory molecules such as FLAME (FLIP) and members of the anti-apoptotic Bcl- 2 family. Third, apoptosis signaling by DR4 and DR5 requires an adaptor molecule distinct from FADD/Mort-1, that could also play a role in the sensitivity of cells to TRAIL-induced apoptosis by analyzing the level of expression of these receptors I various tumor cells to TRAIL-induced apoptosis by analyzing the level of expression of these receptors in various tumor cell lines as well as in normal tissues or cells. Finally, it is proposed to analyze the role of specific antiapoptotic proteins in regulating the TRAIL signaling pathway, and identify and clone the interacting partner (s) of DR4 and DR5. It is anticipated that these studies will contribute to elucidation of the mechanism of signaling by TRAIL-receptors and their biological functions. This could lay the foundation for new therapeutic approaches to cancer.