Ultradian oscillations of Stat, Smad, and Hes1 expression in response to serum.
Serum response has been used as a model for studying signaling transduction for many biological events such as cell proliferation and survival. Although expression of many genes is up- or down-regulated after serum stimulation, the Notch effector Hes1 displays oscillatory response. However, the precise mechanism and biological significance of this oscillation remain to be determined. Here, we identified serum-induced ultradian oscillators, including molecules in Stat and Smad signaling. Stat and Smad oscillations involve activation of Stat3 and Smad1 and delayed negative feedback by their inhibitors Socs3 and Smad6, respectively. Moreover, Stat oscillations induce oscillatory expression of Hes1 by regulating its half-life, and loss of Hes1 oscillations leads to G(1) phase retardation of the cell cycle. These results indicate that coupled Stat and Hes1 oscillations are important for efficient cell proliferation and provide evidence that expression modes of signaling molecules affect downstream cellular events.
Yoshiura
Shigeki
S
Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
Ohtsuka
Toshiyuki
T
Takenaka
Yoshiko
Y
Nagahara
Hiroki
H
Yoshikawa
Kenichi
K
Kageyama
Ryoichiro
R
D000204:Activity Cycles / Q000502:physiology*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D003198:Computer Simulation; D005786:Gene Expression Regulation / Q000502:physiology; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D050791:STAT Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D044967:Serum / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D051785:Smad Proteins / Q000096:biosynthesis / Q000235:genetics*; D000072056:Transcription Factor HES-1
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D050791:STAT Transcription Factors; D051785:Smad Proteins; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse