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.
?-crystallins are multifunction molecules and play indispensable roles in lens transparency. One of such roles is to suppress abnormal apoptosis in the developing or adult lenses induced by endogenous or exogenous factors at multiple signaling steps and pathways to ensure normal differentiation and transparency of the eye lens. The present proposal aims at delineating the functional mechanisms of ?-crystallins in regulating these different signaling steps and pathways to control lens differentiation and guard lens pathogenesis.
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