View source for CREB

{{Short description|Class of proteins}}
{{distinguish|Clean Renewable Energy Bonds}}
{{Use dmy dates|date=March 2014}}
[[File:CREB protein.png|alt=|thumb|200x200px|CREB (top) is a [[transcription factor]] capable of binding [[DNA]] (bottom) and regulating [[gene expression]].]]
'''CREB-TF''' (CREB, '''cAMP response element-binding protein''')<ref name="ReferenceA">{{cite journal | last1 = Bourtchuladze |display-authors=et al | year = 1994| title = Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein | journal = Cell | volume = 79 | issue = 1| pages = 59–68 | pmid = 7923378 | doi=10.1016/0092-8674(94)90400-6|s2cid=17250247 }}</ref> is a cellular [[transcription factor]]. It binds to certain [[DNA]] sequences called cAMP response elements (CRE), thereby increasing or decreasing the [[transcription (genetics)|transcription]] of the [[gene]]s.<ref name="Purves" >{{cite book | author = Purves, Dale | author2 = George J. Augustine | author3 = David Fitzpatrick | author4 = William C. Hall | author5 = Anthony-Samuel LaMantia | author6 = James O. McNamara | author7 = Leonard E. White | name-list-style = amp | title = Neuroscience | edition = 4th | publisher = Sinauer Associates | pages = 170–6 | year = 2008 | isbn = 978-0-87893-697-7}}</ref> CREB was first described in 1987 as a [[cyclic adenosine monophosphate|cAMP]]-responsive transcription factor regulating the [[somatostatin]] gene.<ref>{{Cite journal |title = Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene. |journal = Nature |date = 1987 |pages = 175–178 |volume = 328
|issue = 6126 |first1 = MR |last1 = Montminy|first2 = LM |last2 = Bilezikjian |doi = 10.1038/328175a0 |pmid = 2885756 |bibcode = 1987Natur.328..175M |s2cid = 4345292 }}</ref>

Genes whose transcription is regulated by CREB include: ''[[c-fos]]'', [[BDNF]], [[tyrosine hydroxylase]], numerous [[neuropeptide]]s (such as [[somatostatin]], [[enkephalin]], [[VGF]], [[corticotropin-releasing hormone]]),<ref name="Purves" /> and genes involved in the mammalian [[circadian clock]] ([[PER1]], [[PER2]]).<ref name=":0">{{Cite journal|title = The Mammalian Circadian Timing System: Organization and Coordination of Central and Peripheral Clocks|journal = Annual Review of Physiology|date = 2010|pmid = 20148687|pages = 517–549|volume = 72|issue = 1|doi = 10.1146/annurev-physiol-021909-135821|first1 = Charna|last1 = Dibner|first2 = Ueli|last2 = Schibler|first3 = Urs|last3 = Albrecht|url = http://doc.rero.ch/record/17505/files/alb_mct.pdf}}</ref>

CREB is closely related in structure and function to [[CAMP responsive element modulator|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 [[Neuroplasticity|neuronal plasticity]] and [[long-term memory]] formation in the brain and has been shown to be integral in the formation of [[spatial memory]].<ref>{{cite journal | last1 = Silva | display-authors = etal | year = 1998 | title = CREB and Memory | url = http://www.silvalab.com.cnchost.com/Silva-annrevneurcreb.pdf | journal = Annual Review of Neuroscience | volume = 21 | pages = 127–148 | doi = 10.1146/annurev.neuro.21.1.127 | pmid = 9530494 | access-date = 22 January 2010 | archive-url = https://web.archive.org/web/20080828110737/http://www.silvalab.com.cnchost.com/Silva-annrevneurcreb.pdf | archive-date = 28 August 2008 | url-status = dead }}</ref> 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.<ref>Downregulation of CREB expression in Alzheimer's brain and in Ab-treated rat hippocampal neurons</ref> CREB also has a role in [[Entrainment (chronobiology)|photoentrainment]] in mammals.

==Subtypes==
The following genes encode CREB or CREB-like proteins:
* [[CREB1]] ({{gene|CREB1}})
* CREB2 renamed [[ATF4]] ({{gene|ATF4}})
* [[CREB3]] ({{gene|CREB3}})
* [[CREB5]] ({{gene|CREB5}})
* [[CREB3L1]] ({{gene|CREB3L1}})
* [[CREB3L2]] ({{gene|CREB3L2}})
* [[CREB3L3]] ({{gene|CREB3L3}})
* [[CREB3L4]] ({{gene|CREB3L4}})

==Structure==
[[Image:CREB protein.png|thumb|200px|General structure of the CREB protein]]

CREB proteins are activated by phosphorylation from various kinases, including [[Protein kinase A|PKA]], and [[CAMK|Ca<sup>2+</sup>/calmodulin-dependent protein kinases]] on the Serine 133 residue.<ref>{{Cite journal |title = CREB: A Stimulus-Induced Transcription Factor Activated by A Diverse Array of Extracellular Signals |journal = Annual Review of Biochemistry |date = 1999 |pmid = 10872467 |pages = 821–861 |volume = 68 |issue = 1 |doi = 10.1146/annurev.biochem.68.1.821 |first1 = Adam J. |last1 = Shaywitz |first2 = Michael E. |last2 = Greenberg}}</ref> 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 the [[Leucine zipper|leucine zipper motif]]. The protein also has a magnesium ion that facilitates binding to DNA.

===cAMP response element=== <!--cAMP response element redirects here-->
The ''cAMP response element ''(CRE) is the [[response element]] for CREB which contains the highly conserved nucleotide sequence, 5'-TGACGTCA-3’. CRE sites are typically
found upstream of genes, within the [[Promoter (genetics)|promoter]] or [[Enhancer (genetics)|enhancer]] regions.<ref>{{Cite journal|title = The many faces of CREB|journal =  Trends in Neurosciences|doi=10.1016/j.tins.2005.06.005 |volume=28 |issue = 8 |pages=436–445 |pmid=15982754 |date=August 2005 | last1 = Carlezon | first1 = WA | last2 = Duman | first2 = RS | last3 = Nestler | first3 = EJ|s2cid = 6480593}}</ref> There are approximately 750,000 palindromic and half-site CREs in the human genome. However, the majority of these sites remain unbound due to cytosine [[DNA methylation|methylation]], which physically obstructs protein binding.<ref>{{Cite journal |title = CREB and the CRTC co-activators: sensors for hormonal and metabolic signals |journal = Nature Reviews Molecular Cell Biology |date = March 2011 |issn = 1471-0072 |pmc = 4324555 |pmid = 21346730 |pages = 141–151 |volume = 12 |issue = 3 |doi = 10.1038/nrm3072 |first1 = Judith Y. |last1 = Altarejos |first2 = Marc |last2 = Montminy}}</ref>

==Mechanism of action==
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 a [[second messenger]] such as cAMP or [[calcium|Ca<sup>2+</sup>]], 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 [[CREB-binding protein|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. Evidence suggests the β-adrenoceptor (a [[G protein-coupled receptor|G-protein coupled receptor]]) stimulates CREB signalling.<ref>{{Cite journal|last1=Pearce|first1=Alexander|last2=Sanders|first2=Lucy|last3=Brighton|first3=Paul J.|last4=Rana|first4=Shashi|last5=Konje|first5=Justin C.|last6=Willets|first6=Jonathon M.|date=2017-10-01|title=Reciprocal regulation of β2-adrenoceptor-activated cAMP response-element binding protein signalling by arrestin2 and arrestin3|url=https://figshare.com/articles/journal_contribution/Reciprocal_regulation_of_2-adrenoceptor-activated_cAMP_response-element_binding_protein_signalling_by_arrestin2_and_arrestin3/10213043/1/files/18414974.pdf|journal=Cellular Signalling|language=en|volume=38|pages=182–191|doi=10.1016/j.cellsig.2017.07.011|pmid=28733084 |issn=0898-6568}}</ref>

==Function in the brain==
CREB has many functions in many different organs, and some of its functions have been studied in relation to the brain.<ref name="pmid15982754">{{cite journal |vauthors=Carlezon WA, Duman RS, Nestler EJ |title=The many faces of CREB |journal=Trends in Neurosciences |volume=28 |issue=8 |pages=436–45 |date=August 2005 |pmid=15982754 |doi=10.1016/j.tins.2005.06.005 |s2cid=6480593 }}</ref> CREB proteins in [[neuron]]s are thought to be involved in the formation of long-term memories;<ref>{{Cite journal |last=Kandel |first=Eric R. |date=2012-05-14 |title=The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB |journal=Molecular Brain |volume=5 |pages=14 |doi=10.1186/1756-6606-5-14 |pmid=22583753 |pmc=3514210 |issn=1756-6606 |doi-access=free }}</ref> this has been shown in the marine snail ''[[Aplysia]]'', the fruit fly ''[[Drosophila melanogaster]]'', in [[rattus norvegicus|rats]] and in mice (see [[CREB in Molecular and Cellular Cognition]]).<ref name="ReferenceA"/> CREB is necessary for the late stage of [[long-term potentiation]]. CREB also has an important role in the development of [[drug addiction]] and even more so in [[psychological dependence]].<ref name="pmid19052730">{{cite journal |vauthors=Nazarian A, Sun WL, Zhou L, Kemen LM, Jenab S, Quinones-Jenab V |title=Sex differences in basal and cocaine-induced alterations in PKA and CREB proteins in the nucleus accumbens |journal=Psychopharmacology |volume=203 |issue=3 |pages=641–50 |date=April 2009 |pmid=19052730 |doi=10.1007/s00213-008-1411-5 |s2cid=24064950 }}</ref><ref name="pmid19243452">{{cite journal |vauthors=Wang Y, Ghezzi A, Yin JC, Atkinson NS |title=CREB regulation of BK channel gene expression underlies rapid drug tolerance |journal=Genes, Brain and Behavior |volume=8 |issue=4 |pages=369–76 |date=June 2009 |pmid=19243452 |doi=10.1111/j.1601-183X.2009.00479.x |pmc=2796570}}</ref><ref name="pmid19244515">{{cite journal |vauthors=DiRocco DP, Scheiner ZS, Sindreu CB, Chan GC, Storm DR |title=A role for calmodulin-stimulated adenylyl cyclases in cocaine sensitization |journal=Journal of Neuroscience |volume=29 |issue=8 |pages=2393–403 |date=February 2009 |pmid=19244515 |doi=10.1523/JNEUROSCI.4356-08.2009 |pmc=2678191}}</ref> 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.

==Disease linkage==
Disturbance of CREB function in the 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]].

There is some evidence to suggest that the under-functioning of CREB is associated with [[major depressive disorder]].<ref name="Bel">{{cite journal | last1 = Belmaker | first1 = R. H. | last2 = Agam | first2 = Galila | year = 2008 | title = Major depressive disorder | journal = New England Journal of Medicine | volume = 358 | issue = 1| pages = 55–68 | doi=10.1056/nejmra073096| pmid = 18172175 }}</ref> Depressed rats with an overexpression of CREB in the [[dentate gyrus]] behaved similarly to rats treated with antidepressants.<ref name="Blendy">{{cite journal | last1 = Blendy | first1 = JA | year = 2006 | title = The role of CREB in depression and antidepressant treatment | journal = Biol Psychiatry | volume = 59 | issue = 12| pages = 1144–50 | doi=10.1016/j.biopsych.2005.11.003| pmid = 16457782 | s2cid = 20918484 }}</ref> 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.<ref name="Blendy" />  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.<ref name="Bel" />

CREB is also thought to be involved in the growth of some types of cancer.

== Involvement in circadian rhythms ==
[[Entrainment (chronobiology)|Entrainment]] of the mammalian circadian clock is established via light induction of [[Period (gene)|PER]]. Light excites [[melanopsin]]-containing [[Intrinsically photosensitive retinal ganglion cells|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 receptor]]s on SCN, resulting in a calcium influx into the SCN. Calcium induces the activity of Ca<sup>2+</sup>/[[CAMK|calmodulin-dependent protein kinases]], resulting in the activation of [[Protein kinase A|PKA]], [[Protein kinase C|PKC]], and [[Casein kinase 2|CK2]].<ref>{{Cite journal|title = Circadian gating of neuronal functionality: a basis for iterative metaplasticity|last1 = Iyer|first1 = Rajashekar|date = September 19, 2014|journal = Frontiers in Systems Neuroscience|doi = 10.3389/fnsys.2014.00164|pmid = 25285070|last2 = Wang|first2 = Tongfei|last3 = Gillette|first3 = Martha|author-link3=Martha Gillette|pmc=4168688|volume=8|pages=164|doi-access = free}}</ref> These kinases then phosphorylate CREB in a circadian manner that further regulates downstream gene expression.<ref>{{Cite journal |last1=Obrietan |first1=Karl |last2=Impey |first2=Soren |last3=Smith |first3=Dave |last4=Athos |first4=Jaime |last5=Storm |first5=Derrick R. |date=April 11, 2002 |title=Circadian regulation of cAMP response element-mediated gene expression in the suprachiasmatic nuclei. |journal= Journal of Biological Chemistry|volume=274 |issue=25 |pages=17748–17756 |doi=10.1074/jbc.274.25.17748 |pmid=10364217|doi-access=free }}<!--|access-date = April 21, 2015--></ref> The phosphorylated CREB recognizes the cAMP Response Element and serves as a transcription factor for [[PER1|Per1]] and [[PER2|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.<ref name=":0" />

=== Discovery of CREB involvement in circadian rhythms ===
[[Michael E. Greenberg|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.<ref>{{Cite journal|title = Regulation of CREB phosphorylation in the suprachiasmatic nucleus by light and a circadian clock|journal = Science|date = April 9, 1993|issn = 0036-8075|pmid = 8097062|pages = 238–241|volume = 260|issue = 5105|doi = 10.1126/science.8097062|first1 = D. D.|last1 = Ginty|first2 = J. M.|last2 = Kornhauser|first3 = M. A.|last3 = Thompson|first4 = H.|last4 = Bading|first5 = K. E.|last5 = Mayo|first6 = J. S.|last6 = Takahashi|first7 = M. E.|last7 = Greenberg|bibcode = 1993Sci...260..238G}}</ref> 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.<ref>{{Cite journal|last1=Gau|first1=Daniel|last2=Lemberger|first2=Thomas|last3=von Gall|first3=Charlotte|last4=Kretz|first4=Oliver|last5=Le Minh|first5=Nguyet|last6=Gass|first6=Peter|last7=Schmid|first7=Wolfgang|last8=Schibler|first8=Ueli|last9=Korf|first9=Horst W.|date=April 11, 2002|title=Phosphorylation of CREB Ser142 Regulates Light-Induced Phase Shifts of the Circadian Clock|journal=Neuron|volume=34|issue=2|pages=245–253|doi=10.1016/S0896-6273(02)00656-6|pmid=11970866|s2cid=14507897|doi-access=free}}<!--|access-date = April 21, 2015--></ref>

==See also==
*[[CREB in cognition]]

==References==
{{reflist|30em}}
;Bibliography
#{{cite book |author=Lauren Slater |title=Opening Skinner's Box: Great Psychological Experiments of the Twentieth Century |publisher=W. W. Norton & Company |location=New York |year=2005 |isbn=978-0-393-32655-0 }}
#{{cite journal |vauthors=Barco A, Bailey C, Kandel E |title=Common molecular mechanisms in explicit and implicit memory |journal=J. Neurochem. |volume=97 |issue=6 |pages=1520–33 |year=2006 |pmid=16805766 |doi=10.1111/j.1471-4159.2006.03870.x|doi-access=free }}
#{{cite journal |vauthors=Conkright M, Montminy M |title=CREB: the unindicted cancer co-conspirator |journal=Trends Cell Biol. |volume=15 |issue=9 |pages=457–9 |year=2005 |pmid=16084096 |doi=10.1016/j.tcb.2005.07.007}}
#{{cite journal |vauthors=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 |title=Disruption of CREB function in brain leads to neurodegeneration |journal=Nat. Genet. |volume=31 |issue=1 |pages=47–54 |year=2002 |pmid=11967539 |doi=10.1038/ng882|s2cid=22014116 |doi-access=free }}
#{{cite journal |vauthors=Mayr B, Montminy M |title=Transcriptional regulation by the phosphorylation-dependent factor CREB |journal=Nat. Rev. Mol. Cell Biol. |volume=2 |issue=8 |pages=599–609 |year=2001 |pmid=11483993 |doi=10.1038/35085068|s2cid=1056720 }}
#{{cite journal |vauthors=Yin J, Del Vecchio M, Zhou H, Tully T |title=CREB as a memory modulator: induced expression of a dCREB2 activator isoform enhances long-term memory in Drosophila |journal=Cell |volume=81 |issue=1 |pages=107–15 |year=1995 |pmid=7720066 |doi=10.1016/0092-8674(95)90375-5|s2cid=15863948 |doi-access=free }}
#{{cite journal |vauthors=Yin J, Wallach J, Del Vecchio M, Wilder E, Zhou H, Quinn W, Tully T |title=Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila |journal=Cell |volume=79 |issue=1 |pages=49–58 |year=1994 |pmid=7923376 |doi=10.1016/0092-8674(94)90399-9|s2cid=33623585 }}

==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
* {{MeshName|CREB+Protein}}
* [http://www.sdbonline.org/fly/dbzhnsky/dcreba1.htm ''Drosophila'' ''Cyclic-AMP response element binding protein A'' - The Interactive Fly]
* [http://www.sdbonline.org/fly/neural/dcreb2.htm ''Drosophila'' ''Cyclic-AMP response element binding protein B at 17A'' - The Interactive Fly]

{{Protein domains}}
{{Transcription factors|g1}}

{{DEFAULTSORT:Creb}}
[[Category:Transcription factors]]
[[Category:Addiction|Δ0]]