STAT-1 Interacts with p53 to Enhance DNA Damage-induced Apoptosis

• Published in: The Journal of biological chemistry Vol. 279; no. 7; pp. 5811 - 5820
• Main Authors: Townsend, Paul A., Scarabelli, Tiziano M., Davidson, Sean M., Knight, Richard A., Latchman, David S., Stephanou, Anastasis
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13-02-2004; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Apoptosis; Binding Sites; Blotting, Western; Cyclin-Dependent Kinase Inhibitor p16; DNA Damage; DNA-Binding Proteins - metabolism; Fas antigen; Genes, Reporter; Glutathione Transferase - metabolism; Humans; Interferon-gamma - metabolism; Mdm2 protein; Mice; Mice, Transgenic; Microscopy, Confocal; Mutation; Noxa protein; Nuclear Proteins; Phosphorylation; Precipitin Tests; Promoter Regions, Genetic; Protein Structure, Tertiary; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-mdm2; Recombinant Fusion Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; STAT1 Transcription Factor; Time Factors; Trans-Activators - metabolism; Transcription, Genetic; Transfection; Tumor Suppressor Protein p14ARF - metabolism; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M302637200

The STAT-1 transcription factor has been implicated as a tumor suppressor by virtue of its ability to inhibit cell growth and promoting apoptosis. However, the mechanisms by which STAT-1 mediates these effects remain unclear. Using human and mouse STAT-1-deficient cells, we show here that STAT-1 is required for optimal DNA damage-induced apoptosis. The basal level of the p53 inhibitor Mdm2 is increased in STAT-1(-/-) cells, suggesting that STAT-1 is a negative regulator of Mdm2 expression. Correspondingly, both basal p53 levels, and those induced by DNA damage were lower in STAT-1(-/-) cells. In agreement with this lower p53 response to DNA damage in cells lacking STAT-1, the induction of p53 responsive genes, such as Bax, Noxa, and Fas, was reduced in STAT-1-deficient cells. Conversely, STAT-1 overexpression enhances transcription of these genes, an effect that is abolished if the p53 response element in their promoters is mutated. Moreover, STAT-1 interacts directly with p53, an association, which is enhanced following DNA damage. Therefore, in addition to negatively regulating Mdm2, STAT-1 also acts as a coactivator for p53. Hence STAT-1 is another member of a growing family of protein partners able to modulate the p53-activated apoptotic pathway.