Expression of p14ARF overcomes tumor resistance to p53.
Tumors without p53 mutation are often resistant to p53 gene therapy. We examined the mechanism using p53-resistant A549 cells and p53-sensitive H1299 cells. We found that p53 delivered by adenovirus is poorly expressed in A549 (ARF-null) cells but efficiently expressed in H1299 cells (ARF-positive). Strong p53 expression and apoptosis can be achieved in A549 cells using a p53 mutant resistant to degradation by MDM2 or by coexpression of ARF. The results suggest that enhanced MDM2 activity attributable to loss of ARF contributes to p53 resistance. Surprisingly, tumor cell lines with MDM2 gene amplification are still deficient for ARF expression, suggesting that MDM2 amplification does not substitute for ARF inactivation during tumor development.
Lu
Wenge
W
Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
Lin
Jiayuh
J
Chen
Jiandong
J
D017209:Apoptosis; D005784:Gene Amplification; D016158:Genes, p53; D015316:Genetic Therapy; D006801:Humans; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2