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

  • Li, David W, (PI)

Project: Research project

Description

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.
StatusFinished
Effective start/end date6/1/095/31/12

Funding

  • National Institutes of Health: $515,981.00
  • National Institutes of Health: $512,475.00

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alpha-Crystallins
Crystallins
Apoptosis
Caspase 3
Lenses
Caspase 6
Chaperonin 60
Crystalline Lens
MAP Kinase Signaling System
Heat-Shock Proteins
Cardiac Myocytes
Neuroglia
Astrocytes
Cataract
Mitochondria
Up-Regulation
Epithelial Cells
Pathology

ASJC

  • Medicine(all)