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(The FASEB Journal. 2001;15:221-229.)
© 2001 FASEB

Lens epithelial cells derived from {alpha}B-crystallin knockout mice demonstrate hyperproliferation and genomic instability

U. P. ANDLEY*,{dagger}1, Z. SONG*, E. F. WAWROUSEK, J. P. BRADY,2, S. BASSNETT*,{ddagger} and T. P. FLEMING*,§

Departments of
* Ophthalmology and Visual Sciences,
{dagger} Biochemistry and Molecular Biophysics,
{ddagger} Cell Biology and Physiology and
§ Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA; and
National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA

1Correspondence: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8096, St. Louis, MO 63110, USA. E-mail: andley{at}vision.wustl.edu

{alpha}B-crystallin is a member of the small heat shock protein family and can act as a molecular chaperone preventing the in vitro aggregation of other proteins denatured by heat or other stress conditions. Expression of {alpha}B-crystallin increases in cells exposed to stress and enhanced in tumors of neuroectodermal origin and in many neurodegenerative diseases. In the present study, we examined the properties of lens epithelial cells derived from mice in which the {alpha}B-crystallin gene had been knocked out. Primary rodent cells immortalize spontaneously in tissue culture with a frequency of 10-5 to 10-6. Primary lens epithelial cells derived from {alpha}B-crystallin-/- mice produced hyperproliferative clones at a frequency of 7.6 x 10-2, four orders of magnitude greater than predicted by spontaneous immortalization (1) . Hyperproliferative {alpha}B-crystallin-/- cells were shown to be truly immortal since they have been passaged for more than 100 population doublings without any diminution in growth potential. In striking contrast to the wild-type cells, which were diploid, the {alpha}B-crystallin-/- cultures had a high proportion of tetraploid and higher ploidy cells, indicating that the loss of {alpha}B-crystallin is associated with an increase in genomic instability. Further evidence of genomic instability of {alpha}B-crystallin-/- cells was observed when primary cultures were infected with Ad12-SV40 hybrid virus. In striking contrast to wild-type cells, {alpha}B-crystallin-/- cells expressing SV40 T antigen exhibited a widespread cytocidal response 2 to 3 days after attaining confluence, indicating that SV40 T antigen enhanced the intrinsic genomic instability of {alpha}B-crystallin-/- lens epithelial cells. These observations suggest that the widely distributed molecular chaperone {alpha}B-crystallin may play an important nuclear role in maintaining genomic integrity.—Andley, U. P., Song,, Z., Wawrousek, E. F., Brady, J. P., Bassnett, S., Fleming, T. P. Lens epithelial cells derived from {alpha}B-crystallin knockout mice demonstrate hyperproliferation and genomic instability.


Key Words: molecular chaperone • nuclear • immortalization • ploidy




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