Skin epidermis lacking the c-Myc gene is resistant to Ras-driven tumorigenesis but can reacquire sensitivity upon additional loss of the p21Cip1 gene.
Fiche publication
Date publication
août 2006
Journal
Genes & development
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHAMBON Pierre, Dr METZGER Daniel
Tous les auteurs :
Oskarsson T, Essers MA, Dubois N, Offner S, Dubey C, Roger C, Metzger D, Chambon P, Hummler E, Beard P, Trumpp A
Lien Pubmed
Résumé
The target gene(s) required for Myc-mediated tumorigenesis are still elusive. Here we show that while endogenous c-Myc is surprisingly dispensable for skin homeostasis and TPA-induced hyperplasia, c-Myc-deficient epidermis is resistant to Ras-mediated DMBA/TPAinduced tumorigenesis. This is mechanistically linked to p21(Cip1), which is induced in tumors by the activated Ras-ERK pathway but repressed by c-Myc. Acute elimination of c-Myc in established tumors leads to the up-regulation of p21(Cip1), and epidermis lacking both p21(Cip1) and c-Myc reacquires normal sensitivity to DMBA/TPA-induced tumorigenesis. This identifies c-Myc-mediated repression of p21(Cip1) as a key step for Ras-driven epidermal tumorigenesis.
Mots clés
9,10-Dimethyl-1,2-benzanthracene, toxicity, Animals, Cell Transformation, Neoplastic, Cyclin-Dependent Kinase Inhibitor p21, metabolism, Epidermis, metabolism, Female, Gene Expression Regulation, Neoplastic, Genes, ras, physiology, Male, Mice, Mitogen-Activated Protein Kinase 1, metabolism, Mitogen-Activated Protein Kinase 3, metabolism, Proto-Oncogene Proteins c-myc, genetics, Signal Transduction, Skin Neoplasms, chemically induced, Tetradecanoylphorbol Acetate, toxicity, Up-Regulation
Référence
Genes Dev.. 2006 Aug;20(15):2024-9