NFKB AND APOPTOSIS REGULATORY COMPLEXES

描述（逐字摘自研究者摘要）： 调节NF κ B活化在细胞凋亡和炎症中起关键作用。 最近，该实验室描述了克隆的细胞同源物， 马疱疹病毒2型（EHV 2）蛋白E10，并表明这两种蛋白质调节 哺乳动物细胞凋亡和NF κ B活化。这些蛋白质被发现含有N 末端胱天蛋白酶募集结构域（CARD）和新的C末端结构域 因此，将其命名为CLAPs（CARD样凋亡蛋白）。的 细胞和病毒CLAPs通过激活caspase 8的下游来诱导凋亡 Apaf 1半胱天冬酶9途径并通过作用于NF κ B的上游而激活NF κ B 诱导激酶NIK和IKB激酶IKKa。删除卡或 CTD结构域抑制这两种活性。我们认为，这些领域可能 促进与死亡效应子和NF κ B调节分子的相互作用， 两条路都要走。因此，我们概述了研究 CLAP蛋白参与细胞凋亡或NF κ B途径的机制。 特别是，我们想确定CLAP是否与半胱天冬酶9结合， 直接或通过释放细胞色素c通过Apaf 1途径激活它 从线粒体。实验还提出了研究的作用， TNFR信号复合物中的CARD结构域，决定TNFR信号复合物的其他组分。 CLAP NF κ B激活复合物，并确定导致 IKK复合体的激活。最后，还提出了研究作用 CLAP磷酸化在细胞凋亡和NF κ B活化中的作用，并鉴定 CLAP激酶。预计这些研究将有助于 阐明NF κ B活化和细胞凋亡诱导的机制， CLAPs，并鉴定这两种蛋白质中涉及的其他新蛋白质 途径。由于有足够的证据表明这种蛋白质参与了 肿瘤形成和细胞凋亡，这些研究可以为新的 用于治疗某些形式的癌症的化疗方法，其中 这种蛋白质参与，和治疗其他疾病，其中细胞凋亡是 参与病理过程。

DESCRIPTION ( verbatim from investigator's abstract): Molecules that regulate NFKB activation play critical roles in apoptosis and inflammation. Recently this laboratory described the cloning of the cellular homolog of the equine herpesvirus2 (EHV2) protein E10 and showed that both proteins regulate mammalian apoptosis and NFKB activation. These proteins were found to contain N terminal caspase recruitment domains (CARDs) and novel C terminal domains (CTDs) and were therefore named CLAPs (CARD Like Apoptotic Proteins). The cellular and viral CLAPs induce apoptosis downstream of caspase 8 by activating the Apaf 1 caspase 9 pathway and activate NFKB by acting upstream of the NFKB inducing kinase, NIK, and the IKB kinase, IKKa. Deletion of either the CARD or the CTD domain inhibits both activities. We propose that these domains may facilitate interactions with death effector and NFKB regulatory molecules to engage both pathways. Consequently, we outlined experiments to study the mechanism by which the CLAP proteins engage the apoptotic or the NFKB pathway. In particular, we would like to determine whether CLAP engages caspase 9 directly or activates it through the Apaf 1 pathway via release of cytochrome c from the mitochondria. Experiments are also proposed to study the role of the CARD domain in the TNFR signaling complex, determine other components of the CLAP NFKB activation complex and determine the interactions that lead to activation of the IKK complex. Finally, it is also proposed to study the role of CLAP phosphorylation in apoptosis and NFKB activation and to identify the CLAP kinase. It is anticipated that these studies will contribute to elucidation of the mechanism of NFKB activation and apoptosis induction by CLAPs, and identification of other novel proteins involved in these two pathways. Since there is ample evidence for involvement of this protein in tumor formation and apoptosis, these studies could lay the foundation for new chemotherapeutic approaches for treatment of certain forms of cancer in which this protein is involved, and treatment of other diseases in which apoptosis is involved in the pathologic process.