Real-time in vivo imaging of p16Ink4a reveals cross talk with p53

Kimi Yamakoshi, Akiko Takahashi, Fumiko Hirota, Rika Nakayama, Naozumi Ishimaru, Yoshiaki Kubo, David J. Mann, Masako Ohmura, Atsushi Hirao, Hideyuki Saya, Seiji Arase, Yoshio Hayashi, Kazuki Nakao, Mitsuru Matsumoto, Naoko Ohtani, Eiji Hara

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Abstract

Expression of the p16Ink4a tumor suppressor gene, a sensor of oncogenic stress, is up-regulated by a variety of potentially oncogenic stimuli in cultured primary cells. However, because p16Ink4a expression is also induced by tissue culture stress, physiological mechanisms regulating p16Ink4a 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 p16Ink4a expression under various physiological conditions in living mice. In this study, we show that oncogenic insults such as ras activation provoke epigenetic derepression of p16Ink4a 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 p16Ink4a response in check. These results unveil a backup tumor suppressor role for p16Ink4a in the event of p53 inactivation, expanding our understanding of how p16Ink4a expression is regulated in vivo.

Original languageEnglish
Pages (from-to)393-407
Number of pages15
JournalJournal of Cell Biology
Volume186
Issue number3
DOIs
Publication statusPublished - 2009 Aug 10

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Yamakoshi, K., Takahashi, A., Hirota, F., Nakayama, R., Ishimaru, N., Kubo, Y., Mann, D. J., Ohmura, M., Hirao, A., Saya, H., Arase, S., Hayashi, Y., Nakao, K., Matsumoto, M., Ohtani, N., & Hara, E. (2009). Real-time in vivo imaging of p16Ink4a reveals cross talk with p53. Journal of Cell Biology, 186(3), 393-407. https://doi.org/10.1083/jcb.200904105