APOPTOSIS AND A NEW ADAPTER MOLECULE PATHWAY IN GLIOMA

描述：（改编自研究者摘要）细胞凋亡是 癌症的发病机制，因为抑制细胞凋亡的突变促进了 肿瘤的发展，并有助于放射和化疗的抵抗。新 神经胶质瘤迫切需要恢复凋亡机制的治疗， 这些疾病基本上无法治愈，在美国每年有超过2万人死于这种疾病。 这项研究的重点是一组新的相互作用的蛋白质，集中在 多功能衔接蛋白SETA，其仅限于恶性 星形胶质细胞和肿瘤。SETA结合AlP！，的调节剂 细胞凋亡和ALG-2的结合伴侣，其本身是细胞凋亡所需的。 SETA还结合Cbl家族和Grb 2的信号传导蛋白。引入 各种SETA亚型转化为正常星形胶质细胞，体外转化p53-/- 星形胶质细胞和神经胶质瘤衍生细胞系U87 MG表明，SETA本身是一种 细胞凋亡的调节剂。全长SETA蛋白保护星形胶质细胞免受 紫外线诱导的细胞凋亡，而短，推定的显性负SETA蛋白 在这些实验中，这些数据共同支持了 假设胶质瘤中SETA表达抑制细胞凋亡， 有助于这些致命肿瘤的生长和治疗抗性。到 进一步研究SETA，我们建议（1）表征分子 SETA与其结合伴侣之间的相互作用，通过（i）体外结合 研究，（ii）免疫共沉淀实验，和（iii）研究 亚细胞定位此外，我们将（2）研究机制， SETA调节细胞凋亡。为了做到这一点，我们将首先确定（i） 神经胶质细胞和神经胶质瘤细胞表达凋亡的分子调节因子， (ii)它们对哪些凋亡刺激敏感。 根据这些调查结果， 我们将（iv）测试SETA是一种重要的调节剂的假设， 细胞凋亡和（iv）确定哪种凋亡信号通路SETA 影响。 这项研究将有助于对细胞凋亡是如何在 在分子水平上进行调节，并通过新的蛋白质SETA，揭示 新的干预点，可用于治疗目的， 有益于脑肿瘤患者。

DESCRIPTION: (Adapted from the investigator's abstract) Apoptosis is central to the pathogenesis of cancer, because mutations that suppress apoptosis promote tumor development and contribute to radiation and chemotherapy resistance. New treatments that restore apoptotic mechanisms are urgently needed for gliomas, which are largely incurable, and kill over 20,000 a year in the United States. This study focuses on a novel group of interacting proteins, centered on the multifunctional adapter protein SETA, which is restricted to malignant astrocytes and tumors in the adult brain. SETA binds AlP!, a regulator of apoptosis and binding partner of ALG-2, which is itself required for apoptosis. SETA also binds signaling proteins of the Cbl family and Grb2. Introduction of various SETA isoforms into normal astrocytes, in vitro transformed p53-/- astrocytes, and the glioma-derived cell line U87MG showed that SETA is itself a modulator of apoptosis. Full-length SETA protein protected astrocytes from UV-induced apoptosis, while shorter, putative dominant negative SETA proteins sensitized cells in these experiments. Together these data support the hypothesis that SETA expression in gliomas suppresses apoptosis and so contributes to the growth and treatment resistance of these fatal tumors. To investigate SETA further we propose to (1) characterize the molecular interactions between SETA and its binding partners by (i) in vitro binding studies, (ii) co-immunoprecipitation experiments, and (iii) studying sub-cellular localization. In addition we will (2) examine the mechanism by which SETA modulates apoptosis. In order to do this we will first determine (i) which molecular regulators of apoptosis are expressed by glia and glioma cells, and (ii) which apoptotic stimuli they are sensitive to. In the context of these findings we will (iv) test the hypothesis that SETA is an important modulator of apoptosis and (iv) identify which apoptotic signaling pathway SETA impacts. This study will contribute to the general understanding of how apoptosis is regulated at the molecular level, and through the novel protein SETA, reveal new points of intervention that can be exploited for therapeutic purposes to benefit brain tumor patients.