c-Abl is required for development and optimal cell proliferation in the context of p53 deficiency

Young E. Whang, Chris Tran, Cailin Sibley, Randi G. Syljuasen, Nora Rozengurt, William H. McBride, Charles L. Sawyers

Research output: Contribution to journalArticle

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Abstract

The c-Abl tyrosine kinase and the p53 tumor suppressor protein interact functionally and biochemically in cellular genotoxic stress response pathways and are implicated as downstream mediators of ATM (ataxia-telangiectasia mutated). This fact led us to study genetic interactions in vivo between c- Abl and p53 by examining the phenotype of mice and cells deficient in both proteins. c-Abl-null mice show high neonatal mortality and decreased B lymphocytes, whereas p53-null mice are prone to tumor development. Surprisingly, mice doubly deficient in both c-Abl and p53 are not viable, suggesting that c-Abl and p53 together contribute to an essential function required for normal development. Fibroblasts lacking both c-Abl and p53 were similar to fibroblasts deficient in p53 alone, showing loss of the G1/S cell-cycle checkpoint and similar clonogenic survival after ionizing radiation. Fibroblasts deficient in both c-Abl and p53 show reduced growth in culture, as manifested by reduction in the rate of proliferation, saturation density, and colony formation, compared with fibroblasts lacking p53 alone. This defect could be restored by reconstitution of c-Abl expression. Taken together, these results indicate that the ATM phenotype cannot be explained solely by loss of c-Abl and p53 and that c-Abl contributes to enhanced proliferation of p53-deficient cells. Inhibition of c-Abl function may be a therapeutic strategy to target p53-deficient cells selectively.

Original languageEnglish (US)
Pages (from-to)5486-5491
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number10
DOIs
StatePublished - May 9 2000
Externally publishedYes

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Fibroblasts
Cell Proliferation
Ataxia Telangiectasia
G1 Phase Cell Cycle Checkpoints
Phenotype
Tumor Suppressor Protein p53
Infant Mortality
Ionizing Radiation
Protein-Tyrosine Kinases
DNA Damage
B-Lymphocytes
Growth
Neoplasms
Proteins
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

c-Abl is required for development and optimal cell proliferation in the context of p53 deficiency. / Whang, Young E.; Tran, Chris; Sibley, Cailin; Syljuasen, Randi G.; Rozengurt, Nora; McBride, William H.; Sawyers, Charles L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 10, 09.05.2000, p. 5486-5491.

Research output: Contribution to journalArticle

Whang, Young E. ; Tran, Chris ; Sibley, Cailin ; Syljuasen, Randi G. ; Rozengurt, Nora ; McBride, William H. ; Sawyers, Charles L. / c-Abl is required for development and optimal cell proliferation in the context of p53 deficiency. In: Proceedings of the National Academy of Sciences of the United States of America. 2000 ; Vol. 97, No. 10. pp. 5486-5491.
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