p63 and p73 are required for p53-dependent apoptosis in response to DNA damage.
The tumour-suppressor gene p53 is frequently mutated in human cancers and is important in the cellular response to DNA damage. Although the p53 family members p63 and p73 are structurally related to p53, they have not been directly linked to tumour suppression, although they have been implicated in apoptosis. Given the similarity between this family of genes and the ability of p63 and p73 to transactivate p53 target genes, we explore here their role in DNA damage-induced apoptosis. Mouse embryo fibroblasts deficient for one or a combination of p53 family members were sensitized to undergo apoptosis through the expression of the adenovirus E1A oncogene. While using the E1A system facilitated our ability to perform biochemical analyses, we also examined the functions of p63 and p73 using an in vivo system in which apoptosis has been shown to be dependent on p53. Using both systems, we show here that the combined loss of p63 and p73 results in the failure of cells containing functional p53 to undergo apoptosis in response to DNA damage.
Flores
Elsa R
ER
Massachusetts Institute of Technology, Department of Biology and Center for Cancer Research, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
Tsai
Kenneth Y
KY
Crowley
Denise
D
Sengupta
Shomit
S
Yang
Annie
A
McKeon
Frank
F
Jacks
Tyler
T
D017500:Adenovirus E1A Proteins / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002478:Cells, Cultured; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins
D017500:Adenovirus E1A Proteins; C081876:CKAP4 protein, human; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; C000606460:TP73 protein, human; D015534:Trans-Activators; C486419:Trp63 protein, mouse; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins