Skin epidermis lacking the c-myc gene is resistant to Ras-driven tumorigenesis but can reacquire sensitivity upon additional loss of the p21Cip1 gene (original) (raw)

  1. Thordur Oskarsson1,
  2. Marieke Alida Gertruda Essers1,
  3. Nicole Dubois1,
  4. Sandra Offner1,
  5. Christelle Dubey1,
  6. Catherine Roger1,
  7. Daniel Metzger3,
  8. Pierre Chambon3,
  9. Edith Hummler4,
  10. Peter Beard1, and
  11. Andreas Trumpp1,2,5
  12. 1 Genetics and Stem Cell Laboratory, Swiss Institute for Experimental Cancer Research (ISREC) Ch. des Boveresses 155, 1066 Epalinges, Switzerland;
  13. 2 Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, 1015 Lausanne, Switzerland;
  14. 3 Institut de Génétique et de Biologie Moléculaire et Cellulaire and Institut Clinique de la Souris, 67404 Illkirch, France;
  15. 4 Department de Pharmacologie et de Toxicologie, Université de Lausanne, 1005 Lausanne, Switzerland

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 p21Cip1, 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 p21Cip1, and epidermis lacking both p21Cip1 and c-Myc reacquires normal sensitivity to DMBA/TPA-induced tumorigenesis. This identifies c-Myc-mediated repression of p21Cip1 as a key step for Ras-driven epidermal tumorigenesis.

Footnotes