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CREB (cAMP response element binding) is a protein that is a transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE) and thereby increases or decreases the transcription, and thus the expression, of certain genes. CREB was first described in 1987 as a cAMP-responsive transcription factor regulating the somatostatin gene.
Genes whose transcription is regulated by CREB include: c-fos, the neurotrophin BDNF (Brain-derived neurotrophic factor), tyrosine hydroxylase, and many neuropeptides (such as somatostatin, enkephalin, VGF and corticotropin releasing hormone).
CREB is closely related in structure and function to CREM (cAMP response element modulator) and ATF-1 (activating transcription factor-1) proteins. CREB proteins are expressed in many animals, including humans.
The following genes encode CREB or CREB-like proteins:
- CREB1 (CREB1)
- CREB2 renamed ATF2 (ATF2)
- CREB3 (CREB3)
- CREB5 (CREB5)
- CREB3L1 (CREB3L1)
- CREB3L2 (CREB3L2)
- CREB3L3 (CREB3L3)
- CREB3L4 (CREB3L4)
Mechanism of actionEdit
A typical (albeit somewhat simplified) sequence of events is 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 Ca2+, which in turn activates a protein kinase. This protein kinase translocates to the cell nucleus, where it activates a CREB protein. The activated CREB protein then binds to a CRE region, and is then bound to by a CBP (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 picture.
CREB has many functions in many different organs although most of its functions have been studied in relation to the brain. 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, and in rats. They are necessary for the late stage of long term potentiation. CREB also has an important role in the development of drug addiction. 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 survival.
Disturbance of CREB function in brain can contribute to the development and progression of Huntington's Disease. Abnormalities 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 thought to be involved in the growth of some types of cancer.
cAMP response elementEdit
The cAMP response element is the response element for CREB. Since the effects of protein kinase A on the synthesis of proteins work by activating CREB, the cAMP response element is responsible for modulating the effects of protein kinase A that work by protein synthesis.
- ↑ 1.0 1.1 Purves, Dale, George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, James O. McNamara, and Leonard E. White (2008). Neuroscience. 4th ed., 170–6, Sinauer Associates.
- ↑ Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene. Montminy MR and Bilezikjian LM. Nature. 1987 Jul 9-15;328(6126):175-8.
- ↑ Carlezon WA, Duman RS, Nestler EJ (August 2005). The many faces of CREB. Trends in Neurosciences 28 (8): 436–45.
- ↑ 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.
- ↑ Wang Y, Ghezzi A, Yin JC, Atkinson NS (June 2009). CREB regulation of BK channel gene expression underlies rapid drug tolerance. Genes, Brain, and Behavior 8 (4): 369–76.
- ↑ DiRocco DP, Scheiner ZS, Sindreu CB, Chan GC, Storm DR (February 2009). A role for calmodulin-stimulated adenylyl cyclases in cocaine sensitization. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience 29 (8): 2393–403.
- Lauren Slater, (2005). Opening Skinner's Box: Great Psychological Experiments of the Twentieth Century, New York: W. W. Norton & Company.
- Barco A, Bailey C, Kandel E (2006). Common molecular mechanisms in explicit and implicit memory. J. Neurochem. 97 (6): 1520–33.
- Conkright M, Montminy M (2005). CREB: the unindicted cancer co-conspirator. Trends Cell Biol. 15 (9): 457–9.
- Mantamadiotis T, Lemberger T, Bleckmann S, Kern H, Kretz O, Martin Villalba A, Tronche F, Kellendonk C, Gau D, Kapfhammer J, Otto C, Schmid W, Schütz G (2002). Disruption of CREB function in brain leads to neurodegeneration. Nat. Genet. 31 (1): 47–54.
- Mayr B, Montminy M (2001). Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat. Rev. Mol. Cell Biol. 2 (8): 599–609.
- Yin J, Del Vecchio M, Zhou H, Tully T (1995). CREB as a memory modulator: induced expression of a dCREB2 activator isoform enhances long-term memory in Drosophila. Cell 81 (1): 107–15.
- 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.
- Johannessen, M., Pedersen Delghandi, M., and Moens, U. (2004) - What Turns CREB on ? - Cell Signall.; 10:1211-1227. http://www.sigtrans.org/publications/what-turns-creb-on/
- MeSH CREB+Protein
Constitutive androstane receptor - Core binding factor - E2F - Farnesoid X receptor - Kruppel-like factors - Nanog - NF-kB - Oct-4 - P300/CBP - Peroxisome proliferator-activated - PIT-1 - Rho factor - R-SMAD - Sigma factor - Sox2 - Sp1 - STAT protein
Steroid hormone receptors
Type I: Glucocorticoid receptor - Mineralocorticoid receptor - Sex hormone receptor (Androgen receptor, Estrogen receptor, Progesterone receptor)
Type II: Calcitriol receptor - Retinoid receptor (Retinoic acid receptor, Retinoid X receptor) - Thyroid hormone receptor
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