Splicing into Senescence: The Curious Case of p16 and p19 ARF

Abstract

How can the consequences of inactivating p19ARF in the mouse, namely tumorigenesis and cellular immortalization, be reconciled with the compelling evidence derived from human cancers which points to p16, rather than p19ARF, as the critical target? There is certainly ample precedent for striking differences between mouse and human phenotypes, particularly with respect to cancer predisposition. However, given the functional consequences of disrupting p19ARF in the mouse, it would not be unreasonable to expect that its loss may contribute to the transformed phenotype in the many tumors with genomic deletions that span the p16-p19ARF locus (an argument that might be extended to p15 as well). While p16 may be the essential target for malignant transformation in a subset of human cancers, the loss of these adjacent genes may lead to additional phenotypes that may be better understood once their specific functional pathways have been defined.The pendulum now swings back to defining the specific role of p16 in the mouse. It is possible that disruption of exon 1α will have no phenotype, which would attribute cellular immortalization and tumor development uniquely to the loss of p19ARF, and leave us scrambling to explain yet another difference between mouse and man. Alternatively, specific disruption of p16 may lead to a phenotype similar to that reported following targeting of exon 2, since that exon is critical for p16 function and potentially dispensable for the mediation of cell cycle arrest by p19ARF (Quelle et al. 1997xQuelle, D.E., Cheng, M., Ashmun, R.A., and Sherr, C.J. Proc. Natl. Acad. Sci. USA. 1997; 94: 3436–3440CrossRef | PubMed | Scopus (152)See all ReferencesQuelle et al. 1997). The possibility that both p16 and p19ARF might play independent roles in the regulation of cell cycle progression and cellular senescence is particularly intriguing. Cell cycle arrest by p19ARF appears to be abolished in cells lacking p53, suggesting that it somehow acts upstream of p53 (Kamijo et al. 1997xKamijo, T., Zindy, F., Roussel, M.F., Quelle, D.E., Downing, J.R., Ashmun, R.A., Grosveld, G., and Sherr, C.J. Cell, this issue. 1997; 91: 649–659See all ReferencesKamijo et al. 1997). The exact mechanism by which p19ARF interacts with p53 is uncertain. Unlike the exclusive inactivation of p16 and RB, the observation that some tumors arising in p19ARF-null mice have mutations in p53 indicates that inactivation of these two genes is not functionally equivalent. Nonetheless, like RB the p53 pathway has been implicated in cell cycle progression and senescence. And here lies the most startling implication to emerge from the work of Kamijo and colleagues, the possibility that a single gene “p16-p19ARF” may reside at a crossroad of regulation for both RB and p53, through the use, unprecedented in mammalian cells, of overlapping distinct reading frames.