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 downregulated after serum stimulation, the Notch effectorHesl 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 Smadi and delayed negative feedback by their inhibitors Socs3 and Smad6, respectively. Moreover, Stat oscillations induce oscillatory expression of Hesl by regulating its half-life, and loss of Hesl oscillations leads to G, phase retardation of the cell cycle. These results indicate that coupled Stat and Hesl oscillations are important for efficient cell proliferation and provide evidence that expression modes of signaling molecules affect downstream cellular events.