CREB
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CREB-TF (CREB, cAMP response element-binding protein) is a cellular
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
. It binds to certain
DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
s. CREB was first described in 1987 as a cAMP-responsive transcription factor regulating the
somatostatin Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by #Nomenclature, several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G ...
gene. Genes whose transcription is regulated by CREB include: '' c-fos'',
BDNF Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the cano ...
,
tyrosine hydroxylase Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and ...
, numerous
neuropeptide Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...
s (such as
somatostatin Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by #Nomenclature, several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G ...
, enkephalin, VGF,
corticotropin-releasing hormone Corticotropin-releasing hormone (CRH) (also known as corticotropin-releasing factor (CRF) or corticoliberin; corticotropin may also be spelled corticotrophin) is a peptide hormone involved in stress responses. It is a releasing hormone that b ...
), and genes involved in the mammalian
circadian clock A circadian clock, or circadian oscillator, also known as one’s internal alarm clock is a biochemical oscillator that cycles with a stable phase and is synchronized with solar time. Such a clock's ''in vivo'' period is necessarily almost exact ...
(
PER1 Period circadian protein homolog 1 is a protein in humans that is encoded by the ''PER1'' gene. Function The PER1 protein is important to the maintenance of circadian rhythms in cells, and may also play a role in the development of cancer. Thi ...
, PER2). 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 Long-term memory (LTM) is the stage of the Atkinson–Shiffrin memory model in which informative knowledge is held indefinitely. It is defined in contrast to sensory memory, the initial stage, and short-term or working memory, the second stage ...
formation in the brain and has been shown to be integral in the formation of
spatial memory In cognitive psychology and neuroscience, spatial memory is a form of memory responsible for the recording and recovery of information needed to plan a course to a location and to recall the location of an object or the occurrence of an event. Sp ...
. CREB downregulation is implicated in the pathology of
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
and increasing the expression of CREB is being considered as a possible therapeutic target for Alzheimer's disease. CREB also has a role in photoentrainment in mammals.


Subtypes

The following genes encode CREB or CREB-like proteins: * CREB1 () * CREB2 renamed ATF4 () * CREB3 () * CREB5 () * CREB3L1 () * CREB3L2 () * CREB3L3 () * CREB3L4 ()


Structure

CREB proteins are activated by phosphorylation from various kinases, including PKA, and Ca2+/calmodulin-dependent protein kinases on the Serine 133 residue. 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. 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 Methylation, in the chemistry, chemical sciences, is the addition of a methyl group on a substrate (chemistry), substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replac ...
, which physically obstructs protein binding.


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 Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form of cell signaling, encompassing both first m ...
such as cAMP or Ca2+, which in turn activates a
protein kinase A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them ( phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a f ...
. This protein kinase translocates to the
cell nucleus The cell nucleus (; : nuclei) is a membrane-bound organelle found in eukaryote, eukaryotic cell (biology), cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have #Anucleated_cells, ...
, 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 The Basic Leucine Zipper Domain (bZIP domain) is found in many DNA binding eukaryotic proteins. One part of the domain contains a region that mediates sequence specific DNA binding properties and the leucine zipper that is required to hold toge ...
) as depicted in the image. Evidence suggests the β-adrenoceptor (a
G-protein coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large protein family, group of evoluti ...
) stimulates CREB signalling.


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. CREB proteins in
neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
s 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 ''Drosophila melanogaster'' is a species of fly (an insect of the Order (biology), order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly", "pomace fly" ...
'', in
rats Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include ''Neotoma'' (pack rats), '' Bandicota'' (bandicoot ...
and in mice (see CREB in Molecular and Cellular Cognition). CREB is necessary for the late stage of
long-term potentiation In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neuron ...
. CREB also has an important role in the development of
drug addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...
and even more so in psychological dependence. 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 Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. It typically presents as a triad of progressive psychiatric, cognitive, and ...
. 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 Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...
. Depressed rats with an overexpression of CREB in the
dentate gyrus The dentate gyrus (DG) is one of the subfields of the hippocampus, in the hippocampal formation. The hippocampal formation is located in the temporal lobe of the brain, and includes the hippocampus (including CA1 to CA4) subfields, and other su ...
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 Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...
and
noradrenaline Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as a hormone, neurotransmitter and neuromodulator. The name "noradrenaline" (from ...
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.


Involvement in circadian rhythms

Entrainment of the mammalian circadian clock is established via light induction of PER. Light excites
melanopsin Melanopsin is a type of photopigment belonging to a larger family of light-sensitive retinylidene protein, retinal proteins called opsins and encoded by the gene ''Opn4''. In the mammalian retina, there are two additional categories of opsins, b ...
-containing photosensitive retinal ganglion cells which signal to the
suprachiasmatic nucleus The suprachiasmatic nucleus or nuclei (SCN) is a small region of the brain in the hypothalamus, situated directly above the optic chiasm. It is responsible for regulating sleep cycles in animals. Reception of light inputs from photosensitive r ...
(SCN) via the
retinohypothalamic tract In neuroanatomy, the retinohypothalamic tract (RHT) is a photic neural input pathway involved in the circadian rhythms of mammals. The origin of the retinohypothalamic tract is the intrinsically photosensitive retinal ganglion cells (ipRGC), ...
(RHT). Excitation of the RHT signals the release of glutamate which is received by
NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...
s 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. These kinases then phosphorylate CREB in a circadian manner that further regulates downstream gene expression. The phosphorylated CREB recognizes the cAMP Response Element and serves as a transcription factor for
Per1 Period circadian protein homolog 1 is a protein in humans that is encoded by the ''PER1'' gene. Function The PER1 protein is important to the maintenance of circadian rhythms in cells, and may also play a role in the development of cancer. Thi ...
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.


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. 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.


See also

* CREB in cognition


References

;Bibliography # # # # # # #


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 *
''Drosophila'' ''Cyclic-AMP response element binding protein A'' - The Interactive Fly


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