title: Real-time in vivo imaging of p16Ink4a reveals cross talk with p53.
abstract: 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.
authors: The Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors: Kimi
authors: K
authors: Yamakoshi
authors: Akiko
authors: A
authors: Takahashi
authors: Fumiko
authors: F
authors: Hirota
authors: Rika
authors: R
authors: Nakayama
authors: Naozumi
authors: N
authors: Ishimaru
authors: Yoshiaki
authors: Y
authors: Kubo
authors: David J
authors: DJ
authors: Mann
authors: Masako
authors: M
authors: Ohmura
authors: Atsushi
authors: A
authors: Hirao
authors: Hideyuki
authors: H
authors: Saya
authors: Seiji
authors: S
authors: Arase
authors: Yoshio
authors: Y
authors: Hayashi
authors: Kazuki
authors: K
authors: Nakao
authors: Mitsuru
authors: M
authors: Matsumoto
authors: Naoko
authors: N
authors: Ohtani
authors: Eiji
authors: E
authors: Hara
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D016159:Tumor Suppressor Protein p53