APOPTOSIS AND A NEW ADAPTER MOLECULE PATHWAY IN GLIOMA

描述：(改编自研究人员的摘要)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，并导致放射和化疗耐药性。新的 胶质瘤迫切需要恢复凋亡机制的治疗， 这种疾病在很大程度上是无法治愈的，在美国每年导致超过2万人死亡。 这项研究集中在一组新的相互作用的蛋白质上，集中在 多功能接合蛋白SETA，仅限于恶性 成人大脑中的星形胶质细胞和肿瘤。Seta绑定ALP！，它是一种 细胞凋亡和ALG-2的结合伙伴，而ALG-2本身是细胞凋亡所必需的。 SetA还结合Cb1家族和Grb2的信号蛋白。介绍 不同SETA亚型转化为正常星形胶质细胞，体外转化P53-/- 星形胶质细胞和胶质瘤细胞系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 紫外线诱导的细胞凋亡，而较短的、推测为显性负的SETA蛋白 在这些实验中使细胞敏化。这些数据加在一起支持 脑胶质瘤中SETA表达抑制细胞凋亡的假说 导致这些致命肿瘤的生长和治疗耐药性。至 进一步研究SETA，我们建议：(1)表征分子 SETA与其结合体的相互作用：(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，我们还将(2)研究 SetA对细胞凋亡起调控作用。为了做到这一点，我们将首先确定(I)哪一个 细胞凋亡的分子调节因子由胶质细胞和胶质瘤细胞表达，并且 (Ii)它们对哪种凋亡刺激敏感。在这些发现的背景下 我们将(Iv)检验SETA是一个重要的调节因子的假设。 细胞凋亡和(Iv)确定哪条凋亡信号通路SETA 影响。这项研究将有助于全面理解细胞凋亡是如何 在分子水平上调节，并通过新的蛋白质SETA揭示 可用于治疗目的的新的干预点 使脑瘤患者受益。

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.