ARF functions as a melanoma tumor suppressor by inducing p53-independent senescence

doi:10.1073/pnas.0611638104

ARF functions as a melanoma tumor suppressor by inducing p53-independent senescence

^†Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD 20892-4264;
^‡Pathology/Histotechnology Laboratory, SAIC, National Cancer Institute–Frederick Cancer Research and Development Center, Frederick, MD 21702;
^§Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;
^¶Departments of Medicine and Genetics, University of North Carolina School of Medicine, Chapel Hill, NC 27599;
^‖Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands;
^††Departments of Medical Oncology, Medicine, and Genetics, Center for Applied Cancer Science, and Belfer Foundation Institute for Innovative Cancer Science, Dana–Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; and
^‡‡Division of Basic Medical Sciences, St. George's, University of London, London SW17 0RE, United Kingdom

Edited by Charles J. Sherr, St. Jude Children's Research Hospital, Memphis, TN, and approved May 16, 2007 (received for review December 28, 2006)

Abstract

Inactivation of the p53 pathway represents the most common molecular defect of human cancer. But in the setting of melanoma, a highly aggressive and invariably fatal malignancy in its advanced disseminated form, mutation/deletion of p53 is relatively rare, whereas its positive regulator ARF is often lost. Here, we show that genetic deficiency in Arf but not p53 facilitates rapid development of melanoma in a genetically engineered mouse model. This difference is accounted for, at least in part, by the unanticipated observation that, unlike fibroblasts, senescence control in melanocytes is strongly regulated by Arf and not p53. Moreover, oncogenic NRAS collaborates with deficiency in Arf, but not p53, to fully transform melanocytes. Our data demonstrate that ARF and p53, although linked in a common pathway, suppress tumorigenesis through distinct, lineage-dependent mechanisms and suggest that ARF helps restrict melanoma progression by executing the oncogene-induced senescence program in benign nevi. Thus, therapeutics designed to restore wild-type p53 function may be insufficient to counter melanoma and other malignancies in which ARF holds p53-independent tumor suppressor activity.

Footnotes

^§§To whom correspondence may be addressed. E-mail: gmerlino{at}helix.nih.gov or esviders{at}sgul.ac.uk
Author contributions: L.H. and T.I. contributed equally to this work; L.H., D.C.B., E.V.S., and G.M. designed research; L.H., T.I., and E.V.S. performed research; R.D., S.L., N.E.S., P.K., and R.A.D. contributed new reagents/analytic tools; L.H., T.I., M.A., D.C.B., E.V.S., and G.M. analyzed data; and L.H. and G.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0611638104/DC1.
Abbreviations:

CMGM,

complete melanocyte growth medium;

HGF/SF,

hepatocyte growth factor/scatter factor;

HP1γ,

heterochromatin protein-1γ;

RMS,

rhabdomyosarcoma;

SA-β-gal,

senescence-associated acidic β-galactosidase.
Freely available online through the PNAS open access option.