Regulation of Apoptotic Signaling Pathways by Alpha-Crystallins in the Ocular Len

最近的研究表明，α-晶状体蛋白是一种强大的抗细胞凋亡调节因子，可以阻止大量应激因子诱导的细胞凋亡。然而，a-晶状体蛋白抑制细胞凋亡的分子机制在很大程度上仍不清楚，直到我们最近的研究表明，a-晶状体蛋白能够通过几种不同的机制来消除细胞凋亡。首先，通过与原天冬氨酸氨基转移酶-3和部分加工的中间体相互作用，B-晶状体蛋白可以抑制原天冬氨酸氨基转移酶-3的激活，从而防止应激诱导的细胞凋亡。其次，通过与Bax和Bclxs的相互作用，AA-和AB-晶体蛋白可以将它们的移位隔离到线粒体中，从而阻止应激诱导的细胞凋亡。最后，通过抑制RAS/RAF/MEK/ERK信号通路，AB-晶体蛋白能够干预UVA等应激诱导的细胞凋亡。相反，发现AA-晶状体蛋白能够促进Akt生存通路的激活，以对抗UVA和其他应激诱导的细胞凋亡。我们的观察结果得到了众多实验室近期研究的证实。这些实验室的主要发现是：1)αB晶体蛋白与caspase-3及其前体在心肌细胞和神经胶质细胞中相互作用，而不是在晶状体上皮细胞中；2)两种a-晶体蛋白的敲除都导致晶状体纤维细胞区caspase-3和caspase-6表达上调，继发性晶状体纤维细胞解体，导致细胞凋亡和白内障；3)与相同遗传背景的正常小鼠相比，AB(-I-)小鼠星形胶质细胞中的总Erkl12和p38的表达显著增强；最后，热休克蛋白家族的成员Hsp60直接与Bax相互作用；基于这些结果，我们假设a-晶体蛋白可以调节多个步骤和信号通路，这对晶状体分化和晶状体病理都是基础的。

Recent studies have shown that a-crystallins are strong anti-apoptotic regulators, preventing apoptosis induced by a large number of stress factors. However, the molecular mechanisms by which a-crystallins suppress apoptosis remain largely unknown until our recent studies in which we have demonstrated that a-crystallins are capable of abrogating the apoptotic process in several different mechanisms. First, by interacting with procaspase-3 and the partially processed intermediate, a B - crystallin can repress activation of procaspase-3 and thus prevent stress-induced apoptosis. Second, through interactions with Bax and Bcl-Xs, aA- and aB-crystallins can sequester their translocation into mitochondria to block stress-induced apoptosis. Finally, by repressing the RAS/RAF/MEK/ERK signaling pathway, aB-crystallin is able to intervene UVA- and other stress-induced apoptosis. In contrast, aA-crystallin is found capable of promoting activation of the Akt surviving pathway to counteract UVA- and other stress-induced apoptosis. Our observations have been confirmed by recent studies from numerous laboratories. Major findings from these laboratories are 1) alphaBcrystallin interacts with caspase-3 and its precursors in cardiomyocytes and neuroglial cells besides in lens epithelial cells; 2) knockout of both a-crystallins leads to upregulation of caspase-3 and caspase-6 in the fiber cell zone of the ocular lens where secondary lens fiber cell disintegration occurs, causing apoptosis and cataract; 3). The total and phospho-ERKl 12 and p38 are much enhanced in the astrocytes of the aB(-I-) mice than in those from normal mice with the same genetic background; Finally, Member of the heat shock protein family, hsp60, directly interacts with Bax; Based on these results together, we hypothesize that a-crystallins can modulate multiple steps and signaling pathways, which are fundamental to both lens differentiation and lens pathology.