p15(Ink4b) is a critical tumour suppressor in the absence of p16(Ink4a)

Paul Krimpenfort, Annemieke IJpenberg, Ji-Ying Song, Martin van der Valk, Martijn Nawijn, John Zevenhoven, Anton Berns*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    194 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)943-U11
    Number of pages5
    JournalNature
    Volume448
    Issue number7156
    DOIs
    Publication statusPublished - 23-Aug-2007

    Keywords

    • INK4A LOCUS
    • MICE
    • TUMORIGENESIS
    • P19(ARF)
    • INHIBITORS
    • GENES
    • PRODUCT
    • CANCER
    • CELLS
    • P53

    Cite this