Journal
JOURNAL OF CELL BIOLOGY
Volume 186, Issue 3, Pages 393-407Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200904105
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Cell Science Research Foundation
- Mitsubishi Foundation
- Naito Foundation
- Princess Takamatsu Cancer Research Fund
- Takeda Science Foundation
- Vehicle Racing Commemorative Foundation
- Grants-in-Aid for Scientific Research [21390290] Funding Source: KAKEN
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Expression of the p16(Ink4a) tumor suppressor gene, a sensor of oncogenic stress, is up-regulated by a variety of potentially oncogenic stimuli in cultured primary cells. However, because p16(Ink4)a expression is also induced by tissue culture stress, physiological mechanisms regulating p16(Ink4a) expression remain unclear. To eliminate any potential problems arising from tissue culture imposed stress, we used bioluminescence imaging for noninvasive and real-time analysis of p16(Ink4a) expression under various physiological conditions in living mice. In this study, we show that oncogenic insults such as ras activation provoke epigenetic derepression of p16(Ink4a) expression through reduction of DNMT1 (DNA methyl transferase 1) levels as a DNA damage response 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 p16(Ink4a) expression is regulated in vivo.
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