Activation and Inhibition of Apoptotic Pathways by SV5

超出提供的空间。细胞凋亡在副粘病毒的发病机制中起着重要作用，副粘病毒包括许多重要的病原体。副粘病毒激活和抑制细胞凋亡途径的机制尚不清楚。副粘病毒感染可诱导肿瘤坏死因子α(TNF)的产生，并可引起感染细胞的凋亡。猴病毒5(SV5)是一种副粘病毒，不会引起细胞凋亡。然而，SV5缺失了44个氨基酸残基的小分子疏水(SH)基因，导致了一个突变的病毒，诱导了细胞凋亡和增加了肿瘤坏死因子的表达。推测SH蛋白阻断了肿瘤坏死因子激活的细胞凋亡途径，可能定义了一类新的抗细胞凋亡蛋白。这项工作的长期目标是了解副粘病毒如何与宿主细胞凋亡途径相互作用。本研究的主要目的如下：(1)研究SH蛋白抑制肿瘤坏死因子信号转导途径的机制。初步研究表明，SH蛋白足以抑制肿瘤坏死因子信号转导。SH抑制作用的关键残基以及SH与宿主细胞的相互作用将被确定；(2)研究突变病毒感染细胞中肿瘤坏死因子表达增加的机制。病毒感染细胞中肿瘤坏死因子的表达将在转录和翻译水平上进行检测。将鉴定负责激活表达的SV5蛋白；(3)研究其他副粘病毒编码的SH蛋白的抗凋亡功能。将产生含有来自其他副粘病毒的SH基因的SV5，而不是SV5的SH基因。将检测混合SV5病毒的生长特性并分析其诱导细胞凋亡的能力；以及(4)研究SV5的血凝素神经氨酸酶(HN)蛋白对细胞凋亡途径的抑制作用。和SH一样，HN是一种II型膜蛋白，它有一个由16个氨基酸残基组成的小细胞质尾巴。缺失HN尾巴的重组SV5诱导HeLa T4细胞凋亡HN蛋白在抑制细胞凋亡中的作用将被研究。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. Apoptosis plays important roles in pathogenesis of paramyxoviruses which includes many important pathogens. Mechanisms of activation and inhibition of apoptotic pathways by paramyxoviruses are not well understood. Tumor necrosis factor alpha (TNF) can be induced by paramyxovirus infection and can cause apoptosis of infected cells. Simian virus 5 (SV5), a paramyxovirus, does not cause apoptosis. However, deletion of the 44- amino-acid-residue small hydrophobic (SH) gene from SV5 resulted in a mutant virus that induced apoptosis and increased expression of TNF. It is hypothesized that the SH protein blocks apoptotic pathways activated by TNF and the SH protein may define a new class of anti-apoptosis proteins. Long term goals of this work are to understand how paramyxoviruses interact with host cell apoptotic pathways. The proposal focuses on following aims: (1) investigate mechanism of inhibition of TNF signaling pathways by the SH protein. It is shown in the preliminary studies that the SH protein is sufficient to inhibit TNF signaling. Key residues of SH that are important for its inhibitory effect and host cells with which SH interacts will be identified; (2) investigate mechanism of increased expression of TNF in the mutant virus infected cells. Expression of TNF in virus infected cells will be examined at transcriptional and translational levels. SV5 protein responsible for activating expression will be identified; (3) study anti-apoptosis functions of SH proteins encoded by other paramyxoviruses. SV5 containing SH genes from other paramyxoviruses in place of the SH gene of SV5 will be generated. Growth characteristics of the hybrid SV5 viruses will be examined and their abilities to induce apoptosis will be analyzed; and (4) investigate inhibition of apoptotic pathways by the hemagglutinin-neuraminidase (HN) protein of SV5. Like SH, HN, a type II membrane protein, has a small cytoplasmic tail of 16 amino acid residues. A recombinant SV5 with a deletion of the tail of HN induced apoptosis in HeLa T4 cells. The involvement of the HN protein in inhibiting apoptosis will be studied. PERFORMANCE SITE ========================================Section End===========================================