Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
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
-
Proto-Oncogene Proteins c-myc / physiology*
-
Signal Transduction*
-
Skin Neoplasms / chemically induced
-
Skin Neoplasms / pathology*
-
Tetradecanoylphorbol Acetate / toxicity
-
Up-Regulation
Substances
-
Cyclin-Dependent Kinase Inhibitor p21
-
Proto-Oncogene Proteins c-myc
-
9,10-Dimethyl-1,2-benzanthracene
-
Mitogen-Activated Protein Kinase 1
-
Mitogen-Activated Protein Kinase 3
-
Tetradecanoylphorbol Acetate