Real-Time in Vivo Imaging of$p\,16^{Ink4a} $Reveals Cross Talk with p53

• Published in: The Journal of cell biology 2009-08, Vol.186 (3), p.393-407
• Main Authors: Yamakoshi, Kimi, Takahashi, Akiko, Hirota, Fumiko, Nakayama, Rika, Ishimaru, Naozumi, Kubo, Yoshiaki, Mann, David J., Ohmura, Masako, Hirao, Atsushi, Saya, Hideyuki, Arase, Seiji, Hayashi, Yoshio, Nakao, Kazuki, Matsumoto, Mitsuru, Ohtani, Naoko, Hara, Eiji
• Format: Article
• Language: English
• Subjects: Cell cycle; Cellular senescence; DNA; DNA damage; Gene expression; Genes; Genetic loci; Knockout mice; Papilloma; Tumors
• ISSN: 0021-9525
• DOI: 10.1083/jcb.200904105

Expression of the $p\,16^{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 $p\,16^{Ink4a} $ expression is also induced by tissue culture stress, physiological mechanisms regulating $p\,16^{Ink4a} $ expression remain unclear. To eliminate any potential problems arising from tissue cultureimposed stress, we used bioluminescence imaging for noninvasive and real-time analysis of $p\,16^{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 $p\,16^{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 $p\,16^{Ink4a} $ response in check. These results unveil a backup tumor suppressor role for $p\,16^{Ink4a} $ in the event of p53 inactivation, expanding our understanding of how $p\,16^{Ink4a} $ expression is regulated i in vivo.