CREB-TF (CREB,cAMP response element-binding protein)[1] is a cellulartranscription factor. It binds to certainDNA sequences called cAMP response elements (CRE), thereby increasing or decreasing thetranscription of thegenes.[2] CREB was first described in 1987 as acAMP-responsive transcription factor regulating thesomatostatin gene.[3]
CREB has a well-documented role inneuronal plasticity andlong-term memory formation in the brain and has been shown to be integral in the formation ofspatial memory.[5] CREB downregulation is implicated in the pathology ofAlzheimer's disease and increasing the expression of CREB is being considered as a possible therapeutic target for Alzheimer's disease.[6] CREB also has a role inphotoentrainment in mammals.
CREB proteins are activated by phosphorylation from various kinases, includingPKA, andCa2+/calmodulin-dependent protein kinases on the Serine 133 residue.[7] When activated, CREB protein recruits other transcriptional coactivators to bind to CRE promoter 5’ upstream region. Hydrophobic leucine amino acids are located along the inner edge of the alpha helix. These leucine residues tightly bind to leucine residues of another CREB protein forming a dimer. This chain of leucine residues forms theleucine zipper motif. The protein also has a magnesium ion that facilitates binding to DNA.
ThecAMP response element(CRE) is theresponse element for CREB which contains the highly conserved nucleotide sequence, 5'-TGACGTCA-3’. CRE sites are typicallyfound upstream of genes, within thepromoter orenhancer regions.[8] There are approximately 750,000 palindromic and half-site CREs in the human genome. However, the majority of these sites remain unbound due to cytosinemethylation, which physically obstructs protein binding.[9]
A generalized sequence of events is summarized as follows: A signal arrives at the cell surface, activates the corresponding receptor, which leads to the production of asecond messenger such as cAMP orCa2+, which in turn activates aprotein kinase. This protein kinase translocates to thecell nucleus, where it activates a CREB protein. The activated CREB protein then binds to a CRE region, and is then bound to byCBP (CREB-binding protein), which coactivates it, allowing it to switch certain genes on or off. The DNA binding of CREB is mediated via its basic leucine zipper domain (bZIP domain) as depicted in the image. Evidence suggests the β-adrenoceptor (aG-protein coupled receptor) stimulates CREB signalling.[10]
CREB has many functions in many different organs, and some of its functions have been studied in relation to the brain.[11] CREB proteins inneurons are thought to be involved in the formation of long-term memories;[12] this has been shown in the marine snailAplysia, the fruit flyDrosophila melanogaster, inrats and in mice (seeCREB in Molecular and Cellular Cognition).[1] CREB is necessary for the late stage oflong-term potentiation. CREB also has an important role in the development ofdrug addiction and even more so inpsychological dependence.[13][14][15] There are activator and repressor forms of CREB. Flies genetically engineered to overexpress the inactive form of CREB lose their ability to retain long-term memory. CREB is also important for the survival of neurons, as shown in genetically engineered mice, where CREB and CREM were deleted in the brain. If CREB is lost in the whole developing mouse embryo, the mice die immediately after birth, again highlighting the critical role of CREB in promoting neuronal survival.
There is some evidence to suggest that the under-functioning of CREB is associated withmajor depressive disorder.[16] Depressed rats with an overexpression of CREB in thedentate gyrus behaved similarly to rats treated with antidepressants.[17] From post-mortem examinations it has also been shown that the cortices of patients with untreated major depressive disorder contain reduced concentrations of CREB compared to both healthy controls and patients treated with antidepressants.[17] The function of CREB can be modulated via a signalling pathway resulting from the binding ofserotonin andnoradrenaline to post-synaptic G-protein coupled receptors. Dysfunction of these neurotransmitters is also implicated in major depressive disorder.[16]
CREB is also thought to be involved in the growth of some types of cancer.
Entrainment of the mammalian circadian clock is established via light induction ofPER. Light excitesmelanopsin-containingphotosensitive retinal ganglion cells which signal to thesuprachiasmatic nucleus (SCN) via theretinohypothalamic tract (RHT). Excitation of the RHT signals the release of glutamate which is received byNMDA 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 ofPKA,PKC, andCK2.[18] These kinases then phosphorylate CREB in a circadian manner that further regulates downstream gene expression.[19] The phosphorylated CREB recognizes the cAMP Response Element and serves as a transcription factor forPer1 andPer2, 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.[4]
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.[20] 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.[21]
^abPurves, Dale; George J. Augustine; David Fitzpatrick; William C. Hall; Anthony-Samuel LaMantia; James O. McNamara & Leonard E. White (2008).Neuroscience (4th ed.). Sinauer Associates. pp. 170–6.ISBN978-0-87893-697-7.
^Downregulation of CREB expression in Alzheimer's brain and in Ab-treated rat hippocampal neurons
^Shaywitz, Adam J.; Greenberg, Michael E. (1999). "CREB: A Stimulus-Induced Transcription Factor Activated by A Diverse Array of Extracellular Signals".Annual Review of Biochemistry.68 (1):821–861.doi:10.1146/annurev.biochem.68.1.821.PMID10872467.
^Nazarian A, Sun WL, Zhou L, Kemen LM, Jenab S, Quinones-Jenab V (April 2009). "Sex differences in basal and cocaine-induced alterations in PKA and CREB proteins in the nucleus accumbens".Psychopharmacology.203 (3):641–50.doi:10.1007/s00213-008-1411-5.PMID19052730.S2CID24064950.
^abBelmaker, R. H.; Agam, Galila (2008). "Major depressive disorder".New England Journal of Medicine.358 (1):55–68.doi:10.1056/nejmra073096.PMID18172175.
^Ginty, D. D.; Kornhauser, J. M.; Thompson, M. A.; Bading, H.; Mayo, K. E.; Takahashi, J. S.; Greenberg, M. E. (9 April 1993). "Regulation of CREB phosphorylation in the suprachiasmatic nucleus by light and a circadian clock".Science.260 (5105):238–241.Bibcode:1993Sci...260..238G.doi:10.1126/science.8097062.ISSN0036-8075.PMID8097062.
Lauren Slater (2005).Opening Skinner's Box: Great Psychological Experiments of the Twentieth Century. New York: W. W. Norton & Company.ISBN978-0-393-32655-0.
Yin J, Wallach J, Del Vecchio M, Wilder E, Zhou H, Quinn W, Tully T (1994). "Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila".Cell.79 (1):49–58.doi:10.1016/0092-8674(94)90399-9.PMID7923376.S2CID33623585.
