c-Jun Regulates the Stability and Activity of the p53 Homologue, p73

• Published in: The Journal of biological chemistry 2004-10, Vol.279 (43), p.44713-44722
• Main Authors: Toh, Wen Hong, Siddique, M M, Boominathan, Lakshmanane, Lin, Kai Wei, Sabapathy, Kanaga
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Blotting, Western; Cell Line, Tumor; Cells, Cultured; Cisplatin - pharmacology; COS Cells; DNA - metabolism; DNA-Binding Proteins - physiology; Dose-Response Relationship, Drug; Fibroblasts - metabolism; Genes, Tumor Suppressor; Genetic Vectors; Humans; Immunoblotting; Immunoprecipitation; JNK Mitogen-Activated Protein Kinases - physiology; Luciferases - metabolism; Mice; Nuclear Proteins - metabolism; Nuclear Proteins - physiology; Plasmids - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-abl - metabolism; Proto-Oncogene Proteins c-mdm2; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Time Factors; Transcription, Genetic; Transcriptional Activation; Transfection; Transgenes; Tumor Protein p73; Tumor Suppressor Proteins
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M407672200

Chemotherapeutic drugs and stress signals activate p73, the structural and functional homologue of p53, both by transcriptional activation and post-translational modifications. However, cisplatin, a DNA damage-inducing chemotherapeutic agent, is thought to regulate p73 only by affecting its stability through mechanisms involving the MLH-1/c-Abl signaling cascade. Here we show that c-Jun, a component of the AP-1 family of transcription factors, contributes to p73 induction by cisplatin. c- jun –/– cells are defective in p73 induction, and ectopic c-Jun expression augments p73 levels. c-Jun-mediated accumulation of p73 requires the transactivation activity of c-Jun and occurs in a c-Abl- and Mdm2-independent manner. c-Jun expression increases p73 half-life by preventing it from proteasome-mediated degradation, resulting in the potentiation of p73-mediated transcriptional activity. Moreover, mouse fibroblasts lacking c-Jun are resistant to cisplatin-induced apoptosis, and reintroduction of c-Jun restores p73 activation and sensitivity to cisplatin. Furthermore, p73-mediated apoptosis is abrogated in c- jun –/– cells. Together, these findings demonstrate a possible role for c-Jun in regulating p73 function and highlight the importance of the cooperativity between transcription factors in potentiating apoptosis.