Regulation of INK4a/ARF gene locus and its role in cellular senescence

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We developed a bioluminescence imaging system for non-invasive and real-time analysis of p16^<Ink4a> expression in living mice. Using this system, we show that various oncogenic insults provoke epigenetic de-repression of p16^<Ink4a> expression through reduction of DNMT1 levels in vivo. This pathway is accelerated in the absence of p53, indicating that p53 normally holds the p16^<Ink4a> response in check. These results unveil a backup tumor suppressor role for p16^<Ink4a>in the event of p53 inactivation, expanding our understanding of how tumor suppression mechanism is regulated.