Characterization of the Inhibitor of Apoptosis (IAP) Gen

研究：iaps是一个基因家族，在昆虫、鸟类和哺乳动物等多种物种中都高度保守。该蛋白家族的某些成员已被证明可以结合并抑制半胱天冬酶的活性，半胱天冬酶是凋亡细胞死亡的主要刽子手。hILP，也被称为人类X-linked IAP蛋白（XIAP），可阻断多种刺激诱导的细胞凋亡，包括Fas、TNF、紫外线照射和化学毒性药物。最近的数据表明，XIAP/hILP的BIR结构域是caspase结合和抑制所必需的。我们发现XIAP/hILP是一种多功能蛋白，除了抑制细胞凋亡外，还能与I型转化生长因子- β (tgf - β)受体结合，增强tgf - β介导的基因表达。有趣的是，我们的数据表明XIAP/hILP信号依赖于smad，但不依赖于jnk。此外，我们发现XIAP/hILP的信号传导特性可以与caspase结合分离，因为XIAP/hILP的信号传导需要蛋白质的RING和linkp结构域，而不需要BIR结构域。有趣的是，我们发现通过凋亡对tgf - β有反应的细胞在细胞死亡之前表现出XIAP/hILP的快速降解，而tgf - β耐药细胞则保持高水平的XIAP/hILP。我们推测XIAP/hILP的稳定性可能是细胞对tgf - β反应的决定性因素。鉴于肿瘤转化过程中tgf - β通路的频繁失活，我们正在探索药物破坏XIAP/hILP可能降低肿瘤细胞凋亡阈值的可能性。

Research: The iaps are a family of genes that are highly conserved across species as diverse as insects, birds and mammals. Certain members of this protein family have been shown to bind to and inhibit the activity of caspases, the principle executioners of apoptotic cell death. hILP, also known as human X-linked IAP protein (XIAP), blocks apoptosis induced by a wide variety of stimuli including Fas, TNF, UV irradiation and chemotoxic drugs. Recent data have shown that the BIR domains of XIAP/hILP are required for caspase-binding and inhibition. We have found that XIAP/hILP is a multi-functional protein which, in addition to inhibiting apoptosis, also binds to the type I transforming growth factor-beta (TGF-beta) receptor, and enhances TGF-beta-mediated gene expression. Interestingly, our data suggest that XIAP/hILP signals in a SMAD-dependent, but JNK-independent manner. Furthermore, we have found that the signaling properties of XIAP/hILP can be separated from caspase-binding in that signaling by XIAP/hILP requires the RING and linker domains of the protein, but not the BIR domains. Interestingly, we have found that cells which respond to TGF-beta by undergoing apoptosis exhibit a rapid degradation of XIAP/hILP prior to the onset of cell death, while TGF-beta-resistant cells retain high levels of XIAP/hILP. We speculate that the stability of XIAP/hILP may be a determining factor in the cellular response to TGF-beta. Given the frequent inactivation of the TGF-beta pathway in neoplastic tranformation, we are exploring the possibility that pharmacologic disruption of XIAP/hILP may lower the apoptotic threshold of tumor cells.