Dontenwill Monique, Piletz John E, Chen Michael, Baldwin James, Pascal Geraldine, Ronde Philippe, Dupuy Laurence, Greney Hugues, Takeda Ken, Bousquetd Pascal
Pharmacologie et Physicochimie des Interactions Cellulaires et Moléculaires, UMR CNRS 7034, Faculté de Pharmacie, Université Louis Pasteur de Strasbourg, Illkirch, France.
Ann N Y Acad Sci. 2003 Dec;1009:400-12. doi: 10.1196/annals.1304.054.
Active cell death, also known as apoptosis, has been implicated in the pathophysiology of diseases such as cancer, heart failure and neurodegenerative disorders. We report the anti-apoptotic function of IRAS, which was previously shown to bind imidazoline ligands. The amino acid sequence of human IRAS (hIRAS) is unrelated to known proteins, except for rat IRAS and a mouse homologue named nischarin, which binds the alpha5 integrin subunit of the fibronectin receptor. When stably transfected into PC12 cells, hIRAS localizes to the cytosol as a 167 kDa immunoreactive protein. Clonal PC12 cell lines expressing hIRAS displayed normal serum growth responses. However, hIRAS expression led to prolonged cell survival against known apoptotic stimuli: serum starvation or thapsigargin or staurosporine treatments. The apoptotic population of hIRAS-expressing cells was significantly reduced, and this protection was achieved by a decrease in caspase-3 activity, phosphatidylserine translocation, and nuclear fragmentation. Similar protective effect was obtained in COS7 cells transiently transfected with hIRAS. A partial activation of the PI3 kinase pathway is possibly implicated in the anti-apoptotic effect of IRAS. Thus, IRAS appears to represent a previously unknown anti-apoptotic protein involved in the regulation of cell survival.
细胞主动死亡，也称为凋亡，与癌症、心力衰竭和神经退行性疾病等病症的病理生理学有关。我们报告了IRAS的抗凋亡功能，此前已证明它能结合咪唑啉配体。人IRAS（hIRAS）的氨基酸序列与已知蛋白质无关，但与大鼠IRAS和一种名为nischarin的小鼠同源物有关，后者能结合纤连蛋白受体的α5整合素亚基。当稳定转染到PC12细胞中时，hIRAS作为一种167 kDa的免疫反应性蛋白定位于细胞质中。表达hIRAS的克隆PC12细胞系表现出正常的血清生长反应。然而，hIRAS的表达导致细胞在面对已知的凋亡刺激（血清饥饿、毒胡萝卜素或星形孢菌素处理）时存活时间延长。表达hIRAS的细胞的凋亡群体显著减少，这种保护作用是通过降低半胱天冬酶-3活性、磷脂酰丝氨酸易位和核碎片化来实现的。在用hIRAS瞬时转染的COS7细胞中也获得了类似的保护作用。PI3激酶途径的部分激活可能与IRAS的抗凋亡作用有关。因此，IRAS似乎代表了一种以前未知的参与细胞存活调节的抗凋亡蛋白。
