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Real-time in vivo imaging of p16^Ink4a reveals cross talk with p53

¹ The Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan
² Institute of Enzyme Research and ³ Institute of Health Biosciences, The University of Tokushima, Kuramoto-cho, Tokushima 770-8503, Japan
⁴ Center for Developmental Biology, Institute of Physical and Chemical Research, Chuo-ku, Kobe 650-0047, Japan
⁵ Imperial College London, London SW7 2AZ, England, UK
⁶ Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan
⁷ Institute of Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan

Correspondence to Naoko Ohtani: naoko.ohtani{at}jfcr.or.jp; or Eiji Hara: eiji.hara{at}jfcr.or.jp

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^Ink4a 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.

© 2009 Yamakoshi et al.
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Abbreviations used in this paper: BAC, bacterial artificial chromosome; β-gal, β-galactosidase; BLI, bioluminescence imaging; CCD, charge-coupled device; ChIP, chromatin immunoprecipitation; DDR, DNA damage response; DXR, doxorubicin; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; H3K9, histone 3 Lys9; H3K9me2, H3K9 dimethylation; HDF, human diploid fibroblast; LN, lymph node; MEF, mouse embryonic fibroblast; pRb, retinoblastoma tumor suppressor protein; ROS, reactive oxygen species; SA, senescence associated; shRNA, short hairpin RNA.

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This article has been cited by other articles:

• 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. JEM 206: i18-i18 [Full Text]  

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