Skin epidermis lacking the c-Myc gene is resistant to Ras-driven tumorigenesis but can reacquire sensitivity upon additional loss of the p21Cip1 gene.
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.
Oskarsson
Thordur
T
Genetics and Stem Cell Laboratory, Swiss Institute for Experimental Cancer Research (ISREC) Ch. des Boveresses 155, Epalinges, Switzerland.
Essers
Marieke Alida Gertruda
MA
Dubois
Nicole
N
Offner
Sandra
S
Dubey
Christelle
C
Roger
Catherine
C
Metzger
Daniel
D
Chambon
Pierre
P
Hummler
Edith
E
Beard
Peter
P
Trumpp
Andreas
A
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D002471:Cell Transformation, Neoplastic; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000502:physiology*; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D015854:Up-Regulation
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016271:Proto-Oncogene Proteins c-myc; D015127:9,10-Dimethyl-1,2-benzanthracene; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D013755:Tetradecanoylphorbol Acetate