c-Jun regulates the stability and activity of the p53 homologue, p73.
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.
Laboratory of Molecular Carcinogenesis, Division of Cellular and Molecular Research, National Cancer Centre, 11, Hospital Drive, Singapore 169610, Singapore.
Wen Hong
WH
Toh
M M
MM
Siddique
Lakshmanane
L
Boominathan
Kai Wei
KW
Lin
Kanaga
K
Sabapathy
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D019556:COS Cells; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D005822:Genetic Vectors; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D019076:Transgenes; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D004247:DNA; D008156:Luciferases; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D016315:Proto-Oncogene Proteins c-abl; D048031:JNK Mitogen-Activated Protein Kinases; D002945:Cisplatin