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J Biol Chem, Vol. 273, Issue 47, 31252-31261, November 20, 1998
From the Departments of
The Molecular Chaperone
A-Crystallin Enhances Lens Epithelial
Cell Growth and Resistance to UVA Stress
§,,
, and**
Ophthalmology and
Visual Sciences, § Biochemistry and Molecular Biophysics,
** Cell Biology and Physiology, Washington University School of
Medicine, St. Louis, Missouri 63110, and National
Eye Institute, National Institutes of Health,
Bethesda, Maryland 20892
A-Crystallin (A) is a member of
the small heat shock protein (sHSP) family and has the ability to
prevent denatured proteins from aggregating in vitro. Lens
epithelial cells express relatively low levels of A, but in
differentiated fiber cells, A is the most abundant soluble protein.
The lenses of A-knock-out mice develop opacities at an early age,
implying a critical role for A in the maintenance of fiber cell
transparency. However, the function of -crystallin in the lens
epithelium is unknown. To investigate the physiological function of
A in lens epithelial cells, we used the following two systems: A
knock-out (A(
/)) mouse lens epithelial cells and human lens
epithelial cells that overexpress A. The growth rate of
A(/) mouse lens epithelial cells was reduced by 50% compared
with wild type cells. Cell cycle kinetics, measured by
fluorescence-activated cell sorter analysis of propidium iodide-stained
cells, indicated a relative deficiency of A(/) cells in the
G2/M phases. Exposure of mouse lens epithelial cells to
physiological levels of UVA resulted in an increase in the number of
apoptotic cells in the cultures. Four hours after irradiation the
fraction of apoptotic cells in the A(/) cultures was increased
40-fold over wild type. In cells lacking A, UVA exposure modified
F-actin, but actin was protected in cells expressing A. Stably
transfected cell lines overexpressing human A were generated by
transfecting extended life span human lens epithelial cells with the
mammalian expression vector construct pCI-neoA. Cells overexpressing
A were resistant to UVA stress, as determined by clonogenic
survival. A remained cytoplasmic after exposure to either UVA or
thermal stress indicating that, unlike other sHSPs, the protective
effect of A was not associated with its relocalization to the
nucleus. These results indicate that A has important cellular
functions in the lens over and above its well characterized role in refraction.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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