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.

Public Health Relevance

?-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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY018380-02
Application #
7843604
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Araj, Houmam H
Project Start
2009-06-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
2
Fiscal Year
2010
Total Cost
$515,981
Indirect Cost
Name
University of Nebraska Medical Center
Department
Biochemistry
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Liu, Jifang; Luo, Zhongwen; Zhang, Lan et al. (2016) The small heat shock protein ?A-crystallin negatively regulates pancreatic tumorigenesis. Oncotarget 7:65808-65824
Li, David Wan-Cheng (2015) Still water runs deep. Curr Mol Med 15:1-2
Huang, Mi; Li, Duanzhuo; Huang, Yuwen et al. (2015) HSF4 promotes G1/S arrest in human lens epithelial cells by stabilizing p53. Biochim Biophys Acta 1853:1808-17
Wang, Fengfei; Remke, Marc; Bhat, Kruttika et al. (2015) A microRNA-1280/JAG2 network comprises a novel biological target in high-risk medulloblastoma. Oncotarget 6:2709-24
Wan-Cheng Li, David (2014) A new year of excellence. Curr Mol Med 14:1-2
Hu, X-H; Nie, Q; Yi, M et al. (2014) The tumor suppressor, p53 regulates the ?A-crystallin gene during mouse lens development. Curr Mol Med 14:1197-204
Gong, Lili; Ji, Wei-Ke; Hu, Xiao-Hui et al. (2014) Sumoylation differentially regulates Sp1 to control cell differentiation. Proc Natl Acad Sci U S A 111:5574-9
Fu, David; Lv, Xiangmin; Hua, Guohua et al. (2014) YAP regulates cell proliferation, migration, and steroidogenesis in adult granulosa cell tumors. Endocr Relat Cancer 21:297-310
Li, L; Wang, L; Li, T-T et al. (2013) ERK signaling pathway regulates embryonic survival and eye development in goldfish, Carassius auratus. Curr Mol Med 13:959-67
Li, David Wan-Cheng (2013) Editorial: Continue the great journey of success! Curr Mol Med 13:1-2

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