1. Division of Molecular Genetics and Centre for Biomedical Genetics,
2. Department of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
3. These authors contributed equally to this work.
4. Present address: GSF, Institute for Stem Cell Research, D-85764 Munich, Germany.

Correspondence to: Anton Berns¹ Correspondence and requests for materials should be addressed to A.B. (Email: a.berns@nki.nl).

Abstract

The CDKN2b–CDKN2a locus on chromosome 9p21 in human (chromosome 4 in mouse) is frequently lost in cancer. The locus encodes three cell cycle inhibitory proteins: p15^INK4b encoded by CDKN2b, p16^INK4a encoded by CDKN2a and p14^ARF (p19^Arf in mice) encoded by an alternative reading frame of CDKN2a (ref. 1). Whereas the tumour suppressor functions for p16^INK4a and p14^ARF have been firmly established, the role of p15^INK4b remains ambiguous. However, many 9p21 deletions also remove CDKN2b, so we hypothesized a synergistic effect of the combined deficiency for p15^INK4b, p14^ARF and p16^INK4a. Here we report that mice deficient for all three open reading frames (Cdkn2ab^-/-) are more tumour-prone and develop a wider spectrum of tumours than Cdkn2a mutant mice, with a preponderance of skin tumours and soft tissue sarcomas (for example, mesothelioma) frequently composed of mixed cell types and often showing biphasic differentiation. Cdkn2ab^-/- mouse embryonic fibroblasts (MEFs) are substantially more sensitive to oncogenic transformation than Cdkn2a mutant MEFs. Under conditions of stress, p15^Ink4b protein levels are significantly elevated in MEFs deficient for p16^Ink4a. Our data indicate that p15^Ink4b can fulfil a critical backup function for p16^Ink4a and provide an explanation for the frequent loss of the complete CDKN2b–CDKN2a locus in human tumours.

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