Inhibition of v-Abl transformation by p53 and p19ARF.
Tumorigenesis is a multistep process that involves the activation of oncogenes and the inactivation of tumor suppressor genes. The transforming activity of the v-Abl oncogene of Abelson murine leukemia virus (A-MuLV) in immortal cell lines has been well studied, while the effects of v-Abl in primary fibroblasts are less clear. Here we show that v-Abl causes cell cycle arrest in primary mouse embryonic fibroblasts (MEFs) and elevated levels of both p53 and the cyclin-dependent kinase inhibitor p21Cip. p53-/- or p19ARF-/- MEFs were resistant to v-Abl-induced cell cycle arrest. Although wild-type MEFs were resistant to v-Abl transforming activity, p53-/- or p19ARF-/- MEFs were susceptible. The results indicate that loss of p19ARF and p53 function plays an important role during the transformation of primary cells by v-Abl. We suggest that although v-Abl is a potent oncogene, its full potential transforming activity cannot be realized until the ARF-, and p53-dependent growth inhibitory pathway is disabled. We also show that p53 is not the mediator of v-Abl toxicity in immortal fibroblasts and does not determine the susceptibility of immortal fibroblasts to v-Abl transformation.
Cong
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F
Department of Biological Sciences, Columbia University, New York, NY 10025, USA.
Zou
X
X
Hinrichs
K
K
Calame
K
K
Goff
S P
SP
D000011:Abelson murine leukemia virus / Q000235:genetics; D000818:Animals; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D016313:Genes, abl; D016158:Genes, p53; D051379:Mice; D018345:Mice, Knockout; D016374:Oncogene Proteins v-abl / Q000378:metabolism*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*
D016374:Oncogene Proteins v-abl; D011506:Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53