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Molecular and Cellular Biology, December 2002, p. 8135-8143, Vol. 22, No. 23
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.23.8135-8143.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Biallelic Mutations in p16^INK4a Confer Resistance to Ras- and Ets-Induced Senescence in Human Diploid Fibroblasts

Thomas J. Huot,^1, Janice Rowe,¹ Mark Harland,² Sarah Drayton,¹ Sharon Brookes,¹ Chandra Gooptu,² Patricia Purkis,³ Mike Fried,⁴ Veronique Bataille,⁵ Eiji Hara,⁶ Julia Newton-Bishop,² and Gordon Peters^1*

Cancer Research UK London Research Institute, Lincoln's Inn Fields, London WC2A 3PX,¹ Cancer Research UK Genetic Epidemiology Laboratory, St. James University Hospital, Leeds LS9 7TF,² Cancer Research UK Skin Tumour Laboratory, Centre for Cutaneous Research, Royal London School of Medicine, London E1 2AT,³ Dermatology/Twin Research and Genetic Epidemiology Unit, St. Thomas Hospital, London SE1 7EH,⁵ Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, United Kingdom,⁶ University of California at San Francisco Comprehensive Cancer Center, San Francisco, California 94115⁴

Received 24 May 2002/ Returned for modification 10 July 2002/ Accepted 26 August 2002

The INK4a/ARF tumor suppressor locus is implicated in the senescence-like growth arrest provoked by oncogenic Ras in primary cells. INK4a and ARF are distinct proteins encoded by transcripts in which a shared exon is decoded in alternative reading frames. Here we analyze dermal fibroblasts (designated Q34) from an individual carrying independent missense mutations in each copy of the common exon. Both mutations alter the amino acid sequence of INK4a and functionally impair the protein, although they do so to different degrees. Only one of the mutations affects the sequence of ARF, causing an apparently innocuous change near its carboxy terminus. Unlike normal human fibroblasts, Q34 cells are not permanently arrested by Ras or its downstream effectors Ets1 and Ets2. Moreover, ectopic Ras enables the cells to grow as anchorage-independent colonies, and in relatively young Q34 cells anchorage independence can be achieved without addition of telomerase or perturbation of the p53 pathway. Whereas ARF plays the principal role in Ras-induced arrest of mouse fibroblasts, our data imply that INK4a assumes this role in human fibroblasts.

Present address: T.J.H. Genopole, 91057 Evry Cedex, France.

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