CREB

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CREB (top) is a transcription factor capable of binding DNA (bottom) and regulating gene expression. CREB protein.png
CREB (top) is a transcription factor capable of binding DNA (bottom) and regulating gene expression.

CREB-TF (CREB, cAMP response element-binding protein) [1] is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. [2] CREB was first described in 1987 as a cAMP-responsive transcription factor regulating the somatostatin gene. [3]

Contents

Genes whose transcription is regulated by CREB include: c-fos , BDNF, tyrosine hydroxylase, numerous neuropeptides (such as somatostatin, enkephalin, VGF, corticotropin-releasing hormone), [2] and genes involved in the mammalian circadian clock (PER1, PER2). [4]

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 and has been shown to be integral in the formation of spatial memory. [5] 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. [6] CREB also has a role in photoentrainment in mammals.

Subtypes

The following genes encode CREB or CREB-like proteins:

Structure

General structure of the CREB protein. CREB protein.png
General structure of the CREB protein.

CREB proteins are activated by phosphorylation from various kinases, including PKA, and Ca2+/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 the leucine zipper motif. The protein also has a magnesium ion that facilitates binding to DNA.

cAMP response element

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 or enhancer 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 cytosine methylation, which physically obstructs protein binding. [9]

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 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 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) stimulates CREB signalling. [10]

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. [11] CREB proteins in neurons are thought to be involved in the formation of long-term memories; [12] 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). [1] 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. [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.

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. [16] Depressed rats with an overexpression of CREB in the dentate 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 of serotonin and noradrenaline 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.

Involvement in circadian rhythms

Entrainment of the mammalian circadian clock is established via light induction of PER. Light excites melanopsin-containing 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 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 of PKA, PKC, and CK2. [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 for Per1 and 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. [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]

See also

Related Research Articles

<span class="mw-page-title-main">Protein c-Fos</span> Mammalian protein found in Homo sapiens

Protein c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It is encoded in humans by the FOS gene. It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV. It is a part of a bigger Fos family of transcription factors which includes c-Fos, FosB, Fra-1 and Fra-2. It has been mapped to chromosome region 14q21→q31. c-Fos encodes a 62 kDa protein, which forms heterodimer with c-jun, resulting in the formation of AP-1 complex which binds DNA at AP-1 specific sites at the promoter and enhancer regions of target genes and converts extracellular signals into changes of gene expression. It plays an important role in many cellular functions and has been found to be overexpressed in a variety of cancers.

<span class="mw-page-title-main">CLOCK</span> Human protein and coding gene

CLOCK is a gene encoding a basic helix-loop-helix-PAS transcription factor that is known to affect both the persistence and period of circadian rhythms.

Neuromedin B (NMB) is a bombesin-related peptide in mammals. It was originally purified from pig spinal cord, and later shown to be present in human central nervous system and gastrointestinal tract.

An E-box is a DNA response element found in some eukaryotes that acts as a protein-binding site and has been found to regulate gene expression in neurons, muscles, and other tissues. Its specific DNA sequence, CANNTG, with a palindromic canonical sequence of CACGTG, is recognized and bound by transcription factors to initiate gene transcription. Once the transcription factors bind to the promoters through the E-box, other enzymes can bind to the promoter and facilitate transcription from DNA to mRNA.

Period (per) is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving circadian rhythms in eclosion and locomotor activity. Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm.

<span class="mw-page-title-main">Period circadian protein homolog 1</span> Protein-coding gene in the species Homo sapiens

Period circadian protein homolog 1 is a protein in humans that is encoded by the PER1 gene.

<span class="mw-page-title-main">CREB1</span> Mammalian protein found in Homo sapiens

CAMP responsive element binding protein 1, also known as CREB-1, is a protein that in humans is encoded by the CREB1 gene. This protein binds the cAMP response element, a DNA nucleotide sequence present in many viral and cellular promoters. The binding of CREB1 stimulates transcription.

<span class="mw-page-title-main">ATF1</span> Protein-coding gene in humans

Cyclic AMP-dependent transcription factor ATF-1 is a protein that in humans is encoded by the ATF1 gene.

<span class="mw-page-title-main">ATF4</span> Mammalian protein found in Homo sapiens

Activating transcription factor 4 , also known as ATF4, is a protein that in humans is encoded by the ATF4 gene.

<span class="mw-page-title-main">Activating transcription factor 2</span> Protein-coding gene in the species Homo sapiens

Activating transcription factor 2, also known as ATF2, is a protein that, in humans, is encoded by the ATF2 gene.

cAMP responsive element modulator Protein-coding gene in the species Homo sapiens

cAMP responsive element modulator is a protein that in humans is encoded by the CREM gene, and it belongs to the cAMP-responsive element binding protein family. It has multiple isoforms, which act either as repressors or activators. CREB family is important for in regulating transcription in response to various stresses, metabolic and developmental signals. CREM transcription factors also play an important role in many physiological systems, such as cardiac function, circadian rhythms, locomotion and spermatogenesis.

<span class="mw-page-title-main">RPS6KA2</span> Enzyme found in humans

Ribosomal protein S6 kinase alpha-2 is an enzyme that in humans is encoded by the RPS6KA2 gene.

<span class="mw-page-title-main">CRTC1</span> Protein-coding gene in the species Homo sapiens

CREB-regulated transcription coactivator 1 (CRTC1), previously referred to as TORC1 (Transducer Of Regulated CREB activity 1), is a protein that in humans is encoded by the CRTC1 gene. It is expressed in a limited number of tissues that include fetal brain and liver and adult heart, skeletal muscles, liver and salivary glands and various regions of the adult central nervous system.

<span class="mw-page-title-main">CRTC2</span> Protein-coding gene in the species Homo sapiens

CREB regulated transcription coactivator 2, also known as CRTC2, is a protein which in humans is encoded by the CRTC2 gene.

In molecular biology, an oscillating gene is a gene that is expressed in a rhythmic pattern or in periodic cycles. Oscillating genes are usually circadian and can be identified by periodic changes in the state of an organism. Circadian rhythms, controlled by oscillating genes, have a period of approximately 24 hours. For example, plant leaves opening and closing at different times of the day or the sleep-wake schedule of animals can all include circadian rhythms. Other periods are also possible, such as 29.5 days resulting from circalunar rhythms or 12.4 hours resulting from circatidal rhythms. Oscillating genes include both core clock component genes and output genes. A core clock component gene is a gene necessary for to the pacemaker. However, an output oscillating gene, such as the AVP gene, is rhythmic but not necessary to the pacemaker.

Joseph S. Takahashi is a Japanese American neurobiologist and geneticist. Takahashi is a professor at University of Texas Southwestern Medical Center as well as an investigator at the Howard Hughes Medical Institute. Takahashi's research group discovered the genetic basis for the mammalian circadian clock in 1994 and identified the Clock gene in 1997. Takahashi was elected to the National Academy of Sciences in 2003.

miR-132 Non-coding RNA molecule

In molecular biology miR-132 microRNA is a short non-coding RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms, generally reducing protein levels through the cleavage of mRNAs or the repression of their translation. Several targets for miR-132 have been described, including mediators of neurological development, synaptic transmission, inflammation and angiogenesis.

<span class="mw-page-title-main">Casein kinase 1 isoform epsilon</span> Protein and coding gene in humans

Casein kinase I isoform epsilon or CK1ε, is an enzyme that is encoded by the CSNK1E gene in humans. It is the mammalian homolog of doubletime. CK1ε is a serine/threonine protein kinase and is very highly conserved; therefore, this kinase is very similar to other members of the casein kinase 1 family, of which there are seven mammalian isoforms. CK1ε is most similar to CK1δ in structure and function as the two enzymes maintain a high sequence similarity on their regulatory C-terminal and catalytic domains. This gene is a major component of the mammalian oscillator which controls cellular circadian rhythms. CK1ε has also been implicated in modulating various human health issues such as cancer, neurodegenerative diseases, and diabetes.

Transcription-translation feedback loop (TTFL) is a cellular model for explaining circadian rhythms in behavior and physiology. Widely conserved across species, the TTFL is auto-regulatory, in which transcription of clock genes is regulated by their own protein products.

<span class="mw-page-title-main">AVP gene</span> Gene

Arginine Vasopressin (AVP) Gene is a gene whose product is proteolytically cleaved to produce vasopressin, neurophysin II, and a glycoprotein called copeptin. AVP and other AVP-like peptides are found in mammals, as well as mollusks, arthropods, nematodes, and other invertebrate species. In humans, AVP is present on chromosome 20 and plays a role in homeostatic regulation. The products of AVP have many functions that include vasoconstriction, regulating the balance of water in the body, and regulating responses to stress. Expression of AVP is regulated by the Transcription Translation Feedback Loop (TTFL), which is an important part of the circadian system that controls the expression of clock genes. AVP has important implications in the medical field as its products have significant roles throughout body.

References

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  3. ↑ Montminy, MR; Bilezikjian, LM (1987). "Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene". Nature. 328 (6126): 175–178. Bibcode:1987Natur.328..175M. doi:10.1038/328175a0. PMID   2885756. S2CID   4345292.
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  6. ↑ Downregulation of CREB expression in Alzheimer's brain and in Ab-treated rat hippocampal neurons
  7. ↑ 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. PMID   10872467.
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  9. ↑ Altarejos, Judith Y.; Montminy, Marc (March 2011). "CREB and the CRTC co-activators: sensors for hormonal and metabolic signals". Nature Reviews Molecular Cell Biology. 12 (3): 141–151. doi:10.1038/nrm3072. ISSN   1471-0072. PMC   4324555 . PMID   21346730.
  10. ↑ Pearce, Alexander; Sanders, Lucy; Brighton, Paul J.; Rana, Shashi; Konje, Justin C.; Willets, Jonathon M. (1 October 2017). "Reciprocal regulation of β2-adrenoceptor-activated cAMP response-element binding protein signalling by arrestin2 and arrestin3" (PDF). Cellular Signalling. 38: 182–191. doi:10.1016/j.cellsig.2017.07.011. ISSN   0898-6568. PMID   28733084.
  11. ↑ 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. S2CID   6480593.
  12. ↑ Kandel, Eric R. (14 May 2012). "The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB". Molecular Brain. 5: 14. doi: 10.1186/1756-6606-5-14 . ISSN   1756-6606. PMC   3514210 . PMID   22583753.
  13. ↑ 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. S2CID   24064950.
  14. ↑ 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.
  15. ↑ 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.
  16. 1 2 Belmaker, R. H.; Agam, Galila (2008). "Major depressive disorder". New England Journal of Medicine. 358 (1): 55–68. doi:10.1056/nejmra073096. PMID   18172175.
  17. 1 2 Blendy, JA (2006). "The role of CREB in depression and antidepressant treatment". Biol Psychiatry. 59 (12): 1144–50. doi:10.1016/j.biopsych.2005.11.003. PMID   16457782. S2CID   20918484.
  18. ↑ Iyer, Rajashekar; Wang, Tongfei; Gillette, Martha (19 September 2014). "Circadian gating of neuronal functionality: a basis for iterative metaplasticity". Frontiers in Systems Neuroscience. 8: 164. doi: 10.3389/fnsys.2014.00164 . PMC   4168688 . PMID   25285070.
  19. ↑ Obrietan, Karl; Impey, Soren; Smith, Dave; Athos, Jaime; Storm, Derrick R. (11 April 2002). "Circadian regulation of cAMP response element-mediated gene expression in the suprachiasmatic nuclei". Journal of Biological Chemistry. 274 (25): 17748–17756. doi: 10.1074/jbc.274.25.17748 . PMID   10364217.
  20. ↑ 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. ISSN   0036-8075. PMID   8097062.
  21. ↑ Gau, Daniel; Lemberger, Thomas; von Gall, Charlotte; Kretz, Oliver; Le Minh, Nguyet; Gass, Peter; Schmid, Wolfgang; Schibler, Ueli; Korf, Horst W. (11 April 2002). "Phosphorylation of CREB Ser142 Regulates Light-Induced Phase Shifts of the Circadian Clock". Neuron. 34 (2): 245–253. doi: 10.1016/S0896-6273(02)00656-6 . PMID   11970866. S2CID   14507897.
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