Crosstalk between the Rb pathway and AKT signaling forms a quiescence-senescence switch.
Cell-cycle arrest in quiescence and senescence is largely orchestrated by the retinoblastoma (Rb) tumor-suppressor pathway, but the mechanisms underlying the quiescence-senescence switch remain unclear. Here, we show that the crosstalk between the Rb-AKT-signaling pathways forms this switch by controlling the overlapping functions of FoxO3a and FoxM1 transcription factors in cultured fibroblasts. In the absence of mitogenic signals, although FoxM1 expression is repressed by the Rb pathway, FoxO3a prevents reactive oxygen species (ROS) production by maintaining SOD2 expression, leading to quiescence. However, if the Rb pathway is activated in the presence of mitogenic signals, FoxO3a is also inactivated by AKT, thus reducing SOD2 expression and consequently allowing ROS production. This situation elicits senescence through irreparable DNA damage. We demonstrate that this pathway operates in mouse liver, indicating that this machinery may contribute more broadly to tissue homeostasis in vivo.
Division of Cancer Biology, The Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan; Graduate School of Biomedical Science, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
Yoshinori
Y
Imai
Division of Cancer Biology, The Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
Akiko
A
Takahashi
Division of Cancer Biology, The Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
Aki
A
Hanyu
Division of Cancer Biology, The Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
Satoshi
S
Hori
Division of Cancer Biology, The Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
Seidai
S
Sato
Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan.
Kazuhito
K
Naka
Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan.
Atsushi
A
Hirao
Division of Cancer Biology, The Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan; PRESTO, Japan Science Technology Agency, Saitama 332-0012, Japan.
Naoko
N
Ohtani
Division of Cancer Biology, The Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan; CREST, Japan Science Technology Agency, Saitama 332-0012, Japan. Electronic address: eiji.hara@jfcr.or.jp.
Eiji
E
Hara
D000818:Animals; D059447:Cell Cycle Checkpoints; D016922:Cellular Senescence / Q000502:physiology; D004249:DNA Damage; D005260:Female; D000072278:Forkhead Box Protein M1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020239:Receptor Cross-Talk; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C107585:FOXM1 protein, human; C499517:FOXO3 protein, human; D000072278:Forkhead Box Protein M1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt