Transcriptional activation by p53, but not induction of the p21 gene, is essential for oncogene-mediated apoptosis.
The p53 tumor suppressor limits cellular proliferation by inducing either G1 arrest or apoptosis, depending on the cellular context. To determine if these pathways are mechanistically distinct, we have examined the effects of different p53 mutants in p53 null primary mouse embryo fibroblasts. We chose this system as it is highly physiological and ensures that the interpretation of the results will not be confounded by the presence of endogenous p53 or oncoproteins which target p53. Using single cell microinjection assays for both G1 arrest and apoptosis, with loss-of-function and chimeric gain-of-function mutants, we have demonstrated that transcriptional activation is critical for both processes. Replacement of the p53 activation domain with that of VP16, or replacement of the p53 oligomerization domain with that of GCN4, reconstituted both G1 arrest and apoptosis activities. However, despite the importance of transcriptional activation in both processes, the target gene requirements are different. The p21 cyclin-dependent kinase inhibitor, which has been shown to be a direct target of p53 and a component of the radiation-induced G1 arrest response, is dispensable for oncogene-induced apoptosis, suggesting that these two p53-dependent transcriptional pathways are distinct.
Attardi
L D
LD
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge 02139, USA.
Lowe
S W
SW
Brugarolas
J
J
Jacks
T
T
D017500:Adenovirus E1A Proteins / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001665:Binding Sites; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016193:G1 Phase; D051379:Mice; D016296:Mutagenesis; D009857:Oncogenes; D015398:Signal Transduction; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D017500:Adenovirus E1A Proteins; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53