CREB (cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the downstream 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.
CREB has a well-documented role in neuronal plasticity and long-term memory formation in the brain. CREB has been shown to be integral in the formation of spatial memory. In recent experiments it has been demonstrated that CREB may possess therapeutic potential for patients that have Alzheimer's disease.
The following genes encode CREB or CREB-like proteins:
- CREB1 (CREB1)
- CREB2 renamed ATF4 (ATF4)
- CREB3 (CREB3)
- CREB5 (CREB5)
- CREB3L1 (CREB3L1)
- CREB3L2 (CREB3L2)
- CREB3L3 (CREB3L3)
- CREB3L4 (CREB3L4)
When activated CREB protein forms a dimer and binds to the CRE region of DNA. 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 the dimer. This chain of leucine residues forms the leucine zipper motif. The protein also has a magnesium ion that facilitates binding to DNA.
Mechanism of action
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 image.
CREB has many functions in many different organs, and some 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, in rats and in mice (see CREB in Molecular and Cellular Cognition). CREB is 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.
There is some evidence to suggest that the under-functioning of CREB is associated with Major Depressive Disorder. Depressed rats with an overexpression of CREB in the dentate gyrus behaved similarly to rats treated with antidepressants. 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. The function of CREB can be modulated via a signalling pathway resulting from the binding of serotonin and noradrenaline to post-synaptic G-protein coupled receptors. Dysfunction of these neurotransmitters is also implicated in major depressive disorder.
CREB is also thought to be involved in the growth of some types of cancer.
cAMP response element
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.
- Bourtchuladze et al. "Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein." Cell 79(1):59-68
- Purves, Dale, George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, James O. McNamara, and Leonard E. White (2008). Neuroscience. 4th ed. Sinauer Associates. pp. 170–6. ISBN 978-0-87893-697-7.
- 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.
- Silva et al. "CREB and Memory", Annual Review of Neuroscience, 21:127-148
- Downregulation of CREB expression in Alzheimer’s brain and in Ab-treated rat hippocampal neurons
- Carlezon WA, Duman RS, Nestler EJ (August 2005). "The many faces of CREB". Trends in Neurosciences 28 (8): 436–45. doi:10.1016/j.tins.2005.06.005. PMID 15982754.
- 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. PMID 19052730.
- 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. doi:10.1111/j.1601-183X.2009.00479.x. PMC 2796570. PMID 19243452.
- DiRocco DP, Scheiner ZS, Sindreu CB, Chan GC, Storm DR (February 2009). "A role for calmodulin-stimulated adenylyl cyclases in cocaine sensitization". Journal of Neuroscience 29 (8): 2393–403. doi:10.1523/JNEUROSCI.4356-08.2009. PMC 2678191. PMID 19244515.
- Belmaker, R. H., and Galila Agam. "Major depressive disorder." New England Journal of Medicine 358.1 (2008): 55-68.
- Blendy JA. The role of CREB in depression and antidepressant treatment. Biol Psychiatry 2006;59:1144-50.
- Lauren Slater, (2005). Opening Skinner's Box: Great Psychological Experiments of the Twentieth Century. New York: W. W. Norton & Company. ISBN 0-393-32655-1.
- Barco A, Bailey C, Kandel E (2006). "Common molecular mechanisms in explicit and implicit memory". J. Neurochem. 97 (6): 1520–33. doi:10.1111/j.1471-4159.2006.03870.x. PMID 16805766.
- Conkright M, Montminy M (2005). "CREB: the unindicted cancer co-conspirator". Trends Cell Biol. 15 (9): 457–9. doi:10.1016/j.tcb.2005.07.007. PMID 16084096.
- 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. doi:10.1038/ng882. PMID 11967539.
- Mayr B, Montminy M (2001). "Transcriptional regulation by the phosphorylation-dependent factor CREB". Nat. Rev. Mol. Cell Biol. 2 (8): 599–609. doi:10.1038/35085068. PMID 11483993.
- 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. doi:10.1016/0092-8674(95)90375-5. PMID 7720066.
- 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. PMID 7923376.
- 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/
- CREB Protein at the US National Library of Medicine Medical Subject Headings (MeSH)
- Drosophila Cyclic-AMP response element binding protein A - The Interactive Fly
- Drosophila Cyclic-AMP response element binding protein B at 17A - The Interactive Fly