Document Detail

Hyperproliferation and p53 status of lens epithelial cells derived from alphaB-crystallin knockout mice.
MedLine Citation:
PMID:  12826669     Owner:  NLM     Status:  MEDLINE    
alphaB-Crystallin, a major protein of lens fiber cells, is a stress-induced chaperone expressed at low levels in the lens epithelium and numerous other tissues, and its expression is enhanced in certain pathological conditions. However, the function of alphaB in these tissues is not known. Lenses of alphaB-/- mice develop degeneration of specific skeletal muscles but do not develop cataracts. Recent work in our laboratory indicates that primary cultures of alphaB-/- lens epithelial cells demonstrate genomic instability and undergo hyperproliferation at a frequency 4 orders of magnitude greater than that predicted by spontaneous immortalization of rodent cells. We now demonstrate that the hyperproliferative alphaB-/- lens epithelial cells undergo phenotypic changes that include the appearance of the p53 protein as shown by immunoblot analysis. Sequence analysis showed a lack of mutations in the p53 coding region of hyperproliferative alphaB-/- cells. However, the reentry of hyperproliferative alphaB-/- cells into S phase and mitosis after DNA damage by gamma-irradiation were consistent with impaired p53 checkpoint function in these cells. The results demonstrate that expression of functionally impaired p53 is one of the factors that promote immortalization of lens epithelial cells derived from alphaB-/- mice. Fluorescence in situ hybridization using probes prepared from centromere-specific mouse P1 clones of chromosomes 1 and 9 demonstrated that the hyperproliferative alphaB-/- cells were 30% diploid and 70% tetraploid, whereas wild type cells were 83% diploid. Further evidence of genomic instability was obtained when the hyperproliferative alphaB-/- cells were labeled with anti-beta-tubulin antibodies. Examination of the hyperproliferative alphaB-/- mitotic profiles revealed the presence of cells that failed to round up for mitosis, or arrested in cytokinesis, and binucleated cells in which nuclear division had occurred without cell division. These results suggest that the stress protein and molecular chaperone alphaB-crystallin protects cells from acquiring impaired p53 protein and genomic instability.
Fang Bai; Jing Hua Xi; Eric F Wawrousek; Timothy P Fleming; Usha P Andley
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2003-06-25
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  278     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2003 Sep 
Date Detail:
Created Date:  2003-09-15     Completed Date:  2003-11-20     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  36876-86     Citation Subset:  IM    
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
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MeSH Terms
Blotting, Western
Cell Cycle
Cell Death
Cell Division
Cells, Cultured
Centromere / metabolism
DNA / metabolism
DNA, Complementary / metabolism
Epithelial Cells / metabolism*
Gamma Rays
In Situ Hybridization, Fluorescence
Lens, Crystalline / metabolism*
Mice, Knockout
Mice, Transgenic
Microscopy, Fluorescence
Muscle, Skeletal / metabolism
Retinoblastoma Protein / metabolism
Time Factors
Tumor Suppressor Protein p53 / metabolism*
alpha-Crystallin B Chain / genetics*
Grant Support
Reg. No./Substance:
0/DNA, Complementary; 0/Retinoblastoma Protein; 0/Tumor Suppressor Protein p53; 0/alpha-Crystallin B Chain; 9007-49-2/DNA

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