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

Overview

MeSH Major

  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Carcinoma, Non-Small-Cell Lung
  • Drug Resistance, Neoplasm
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Lung Neoplasms
  • Membrane Proteins
  • Polymorphism, Genetic
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Sequence Deletion

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 G(1)/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.

publication date

  • May 9, 2000

Research

keywords

  • Academic Article

Identity

Digital Object Identifier (DOI)

  • 10.1073/pnas.97.10.5486

PubMed ID

  • 10805805

Additional Document Info

start page

  • 5486

end page

  • 91

volume

  • 97

number

  • 10