cancer. Involvement in circadian rhythms Entrainment of the mammalian circadian clock is established via light induction of PER. Light excites melanopsin-containing photosensitive retinal ganglion cells which signal to the suprachiasmatic nucleus (SCN) via the retinohypothalamic tract (RHT). Excitation of the RHT signals the release of glutamate which is received by NMDA receptors on SCN, resulting in a calcium influx into the SCN. Calcium induces the activity of Ca2+/calmodulin-dependent protein kinases, resulting in the activation of PKA, PKC, and CK2. These kinases then phosphorylate CREB in a circadian manner that further regulates downstream gene expression. The phosphorylated CREB recognizes the cAMP Response Element and serves as a transcription factor for Per1 and Per2, two genes that regulate the mammalian circadian clock. This induction of PER protein can entrain the circadian clock to light/dark cycles inhibits its own transcription via a transcription-translation feedback loop which can advance or delay the circadian clock. However, the responsiveness of PER1 and PER2 protein induction is only significant during the subjective night. Discovery of CREB involvement in circadian rhythms Michael Greenberg first demonstrated the role of CREB in the mammalian circadian clock in 1993 through a series of experiments that correlated phase-specific light pulses with CREB phosphorylation. In vitro, light during the subjective night increased phosphorylation of CREB rather than CREB protein levels. In vivo, phase shift-inducing light pulses during the subjective night correlated with CREB phosphorylation in the SCN. Experiments by Gunther Schutz in 2002 demonstrated that mutant mice lacking the Ser142 phosphorylation site failed to induce the clock regulatory gene mPer1 in response to a light pulse. Furthermore, these mutant mice had difficulty entraining to light-dark cycles. See also CREB in cognition References Bibliography External links http://www.ebi.ac.uk/interpro/entry/IPR001630 Johannessen, M., Pedersen Delghandi, M., and Moens, U. (2004) - What Turns CREB on ? - Cell Signall.; 10:1211-1227. https://web.archive.org/web/20070928090058/http://www.sigtrans.org/publications/what-turns-creb-on/ https://web.archive.org/web/20060902183214/http://focus.hms.harvard.edu//2001/Oct26_2001/neuroscience.html Drosophila Cyclic-AMP response element binding protein A - The Interactive Fly Drosophila Cyclic-AMP response element binding protein B at 17A - The Interactive Fly Transcription factors Δ0