![]() There is some evidence to suggest that the under-functioning of CREB is associated with major depressive disorder. 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.ĭisturbance of CREB function in the brain can contribute to the development and progression of Huntington's disease.Ībnormalities of a protein that interacts with the KID domain of CREB, the CREB-binding protein, (CBP) is associated with Rubinstein-Taybi syndrome. CREB is also important for the survival of neurons, as shown in genetically engineered mice, where CREB and CREM were deleted in the brain. ![]() Flies genetically engineered to overexpress the inactive form of CREB lose their ability to retain long-term memory. There are activator and repressor forms of CREB. CREB also has an important role in the development of drug addiction and even more so in psychological dependence. CREB is necessary for the late stage of long-term potentiation. CREB proteins in neurons are thought to be involved in the formation of long-term memories this has been shown in the marine snail Aplysia, the fruit fly Drosophila melanogaster, in rats and in mice (see CREB in Molecular and Cellular Cognition). Function in the brain ĬREB has many functions in many different organs, and some of its functions have been studied in relation to the brain. Evidence suggests the β-adrenoceptor (a G-protein coupled receptor) stimulates CREB signalling. The DNA binding of CREB is mediated via its basic leucine zipper domain ( bZIP domain) as depicted in the image. The activated CREB protein then binds to a CRE region, and is then bound to by CBP (CREB-binding protein), which coactivates it, allowing it to switch certain genes on or off. This protein kinase translocates to the cell nucleus, where it activates a CREB protein. Mechanism of action Ī 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 a second messenger such as cAMP or Ca 2+, which in turn activates a protein kinase. However, the majority of these sites remain unbound due to cytosine methylation, which physically obstructs protein binding. There are approximately 750,000 palindromic and half-site CREs in the human genome. CRE sites are typicallyįound upstream of genes, within the promoter or enhancer regions. The cAMP response element (CRE) is the response element for CREB which contains the highly conserved nucleotide sequence, 5'-TGACGTCA-3’. The protein also has a magnesium ion that facilitates binding to DNA. This chain of leucine residues forms the leucine zipper motif. These leucine residues tightly bind to leucine residues of another CREB protein forming a dimer. Hydrophobic leucine amino acids are located along the inner edge of the alpha helix. When activated, CREB protein recruits other transcriptional coactivators to bind to CRE promoter 5’ upstream region. Structure General structure of the CREB protein.ĬREB proteins are activated by phosphorylation from various kinases, including PKA, and Ca 2+/calmodulin-dependent protein kinases on the Serine 133 residue. The following genes encode CREB or CREB-like proteins: CREB also has a role in photoentrainment in mammals. CREB downregulation is implicated in the pathology of Alzheimer's disease and increasing the expression of CREB is being considered as a possible therapeutic target for Alzheimer's disease. CREB proteins are expressed in many animals, including humans.ĬREB has a well-documented role in neuronal plasticity and long-term memory formation in the brain and has been shown to be integral in the formation of spatial memory. ![]() ĬREB is closely related in structure and function to CREM ( cAMP response element modulator) and ATF-1 ( activating transcription factor-1) proteins. Genes whose transcription is regulated by CREB include: c-fos, BDNF, tyrosine hydroxylase, numerous neuropeptides (such as somatostatin, enkephalin, VGF, corticotropin-releasing hormone), and genes involved in the mammalian circadian clock ( PER1, PER2). ![]() CREB was first described in 1987 as a cAMP-responsive transcription factor regulating the somatostatin gene. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. Not to be confused with Clean Renewable Energy Bonds.ĬREB (top) is a transcription factor capable of binding DNA (bottom) and regulating gene expression.ĬREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor.
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