NFKB AND APOPTOSIS REGULATORY COMPLEXES

描述(逐字摘自研究人员摘要)：分子 调节NFKB的激活在细胞凋亡和炎症中起着关键作用。 最近，这个实验室描述了克隆的细胞同源基因 马疱疹病毒2(EHV2)蛋白E10，并表明这两种蛋白都调节 哺乳动物细胞凋亡和NFKB激活。这些蛋白质被发现含有N Caspase末端募集结构域(CADS)和新的C末端结构域 (CTDS)，因此被命名为CLAPS(卡片状凋亡蛋白)。这个 细胞和病毒CLAP通过激活caspase 8下游诱导细胞凋亡 Apaf-1-caspase-9途径并通过作用于NFKB的上游激活NFKB 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。我们建议这些域可以 促进与死亡效应分子和NFKB调控分子的相互作用 让两条路都接通。因此，我们概述了研究 CLAP蛋白参与细胞凋亡或NFKB途径的机制。 特别是，我们想确定clap是否与caspase 9接合。 通过释放细胞色素c直接或通过apaf1途径激活它。 从线粒体中。此外，还建议进行实验，以研究 在TNFR信号复合体中的Card域，决定了 点击NFKB激活复合体并确定导致 激活IKK复合体。最后，还提出了研究其作用的建议。 CLAP磷酸化在细胞凋亡和NFKB激活中的作用 拍打蛋白激酶。预计这些研究将有助于 NFKB激活和诱导细胞凋亡机制的阐明 以及与这两种蛋白相关的其他新蛋白的鉴定 小路。因为有充分的证据表明这种蛋白质参与了 肿瘤的形成和凋亡，这些研究可能为新的 治疗某些形式的癌症的化疗方法 这种蛋白参与了对其他疾病的治疗，其中细胞凋亡是 参与了病理过程。

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.