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

Thordur Oskarsson; Marieke Alida Gertruda Essers; Nicole Dubois; Sandra Offner; Christelle Dubey; Catherine Roger; Daniel Metzger; Pierre Chambon; Edith Hummler; Peter Beard; Andreas Trumpp

doi:10.1101/gad.381206

Skin epidermis lacking the c-myc gene is resistant to Ras-driven tumorigenesis but can reacquire sensitivity upon additional loss of the p21^Cip1 gene

¹ Genetics and Stem Cell Laboratory, Swiss Institute for Experimental Cancer Research (ISREC) Ch. des Boveresses 155, 1066 Epalinges, Switzerland;
² Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, 1015 Lausanne, Switzerland;
³ Institut de Génétique et de Biologie Moléculaire et Cellulaire and Institut Clinique de la Souris, 67404 Illkirch, France;
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 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.

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Footnotes

↵5 Corresponding author.

↵5 E-MAIL Andreas.Trumpp{at}isrec.ch; FAX 41-21-652-6933.
Supplemental material is available at http://www.genesdev.org.
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.381206
- Received January 24, 2006.
- Accepted May 28, 2006.