Skin epidermis lacking the c-Myc gene is resistant to Ras-driven tumorigenesis but can reacquire sensitivity upon additional loss of the p21Cip1 gene

Genes Dev. 2006 Aug 1;20(15):2024-9. doi: 10.1101/gad.381206.


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


  • 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