Splicing into Senescence: The Curious Case of p16 and p19ARF

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