Entry - *123810 - cAMP RESPONSE ELEMENT-BINDING PROTEIN 1; CREB1 - OMIM

 
 
* 123810

cAMP RESPONSE ELEMENT-BINDING PROTEIN 1; CREB1


Alternative titles; symbols

CREB


Other entities represented in this entry:

CREB/EWS FUSION GENE, INCLUDED

HGNC Approved Gene Symbol: CREB1

Cytogenetic location: 2q33.3     Genomic coordinates (GRCh38): 2:207,529,962-207,605,988 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number 		Inheritance Phenotype
mapping key
2q33.3 Histiocytoma, angiomatoid fibrous, somatic 612160 3

TEXT

▼ Cloning and Expression

Cyclic AMP (cAMP) second messenger pathways provide a chief means by which cellular growth, differentiation, and function can be influenced by extracellular signals. Following hormonal stimulation of a neuroendocrine cell, for example, increased cAMP levels activate cAMP-dependent protein kinase A, which phosphorylates 1 or more DNA-binding proteins. These in turn stimulate transcription of an array of cAMP-responsive genes such as those for somatostatin (182450), alpha-gonadotropin (118850), proenkephalin (131330) and FOS (164810). All cAMP-responsive gene promoters have in common an 8-base enhancer known as the cAMP-response element (CRE) containing a conserved core sequence, 5-prime-TGACG-3-prime, first described in the somatostatin gene by Montminy et al. (1986). Montminy and Bilezikjian (1987) purified a 43-kD nuclear phosphoprotein that bound to CRE with high affinity.

Hoeffler et al. (1988) isolated cDNA clones for human CREB. The deduced 326-amino acid protein has an N-terminal acidic region, a leucine zipper-like sequence, and a C-terminal basic region. The acidic region may be a transcriptional activation domain, and the leucine zipper may bind DNA or DNA-associated proteins.

By PCR of a human peripheral blood T-cell cDNA library, Berkowitz and Gilman (1990) identified 2 variants of CREB1, which they called CREB-A and CREB-B. CREB-A is identical to the CREB variant cloned by Hoeffler et al. (1988). CREB-B encodes a deduced 341-amino acid protein containing a 14-amino acid serine-rich insertion at amino acid 88 of CREB-A. RNase protection assays detected both transcripts in several human cell lines and in rodent cell lines and tissues.

Ruppert et al. (1992) cloned several splice variants of mouse Creb that appeared to have protein-coding potential. The longest isoform, Creb-alpha, contains 341 amino acids, and the most common isoform, Creb-delta, lacks 14 amino acids near the N terminus.


▼ Mapping

By use of a cDNA probe for Southern blot analysis of genomic DNA from a panel of mouse/human somatic cell hybrids and for in situ hybridization, Taylor et al. (1990) mapped CREB1 to 2q32.3-q34. Taylor et al. (1990) speculated about the possible involvement of CREB1 in genetic disorders or cancer and pointed to the fact that TCL4 (186860), a locus implicated in T-cell leukemia/lymphoma, is located at 2q34. Cole et al. (1992) demonstrated that the Creb1 locus maps to the proximal region of mouse chromosome 1. The CREB gene was found to be single copy in the mouse and well conserved through evolution. Barton et al. (1992) mapped the Creb1 gene to mouse chromosome 1 by linkage studies. It was found to be approximately 1 cM distal to Cryg and 7 cM proximal to Vil.


▼ Gene Function

Using an in vitro binding assay, Berkowitz and Gilman (1990) found that both CREB-A and CREB-B specifically bound a cAMP response element. Both bound DNA as dimers and imparted cAMP-regulated transcriptional activity to a heterologous DNA-binding domain. The authors concluded that the 2 isoforms may regulate distinct gene activities.

Transcriptional activity of CREB requires phosphorylation of the protein on a serine residue at position 119. The CRE element (TGANNTCA) to which CREB binds is present in a number of T-cell genes, but the precise role of CREB in T-cell differentiation and function had been unknown. Barton et al. (1996) showed that resting thymocytes contain predominantly unphosphorylated (i.e., inactive) CREB, which is rapidly activated by phosphorylation on ser119 following thymocyte activation. T-cell development is normal in transgenic mice that express a dominant-negative form of CREB (with alanine at position 119) under the control of a T-cell-specific CD2 promoter/enhancer. In contrast, thymocytes and T cells from these animals display a profound proliferative defect characterized by markedly decreased interleukin-2 (IL2; 147680) production, G1 cell cycle arrest, and subsequent apoptotic death in response to a number of different activation signals. Barton et al. (1996) proposed that T-cell activation leads to the phosphorylation and activation of CREB, which in turn is required for the normal induction of the transcription factor AP1 (see 165160) and subsequent interleukin-2 production and cell cycle progression.

Using EMSA analysis, Solomou et al. (2001) showed that while stimulated T cells from normal individuals had increased binding of phosphorylated CREB to the -180 site of the IL2 promoter, nearly all stimulated T cells from systemic lupus erythematosus (SLE; 152700) patients had increased binding primarily of phosphorylated CREM (123812) at this site and to the transcriptional coactivators CREBBP (600140) and EP300 (602700). Increased expression of phosphorylated CREM correlated with decreased production of IL2. Solomou et al. (2001) concluded that transcriptional repression is responsible for the decreased production of IL2 and anergy in SLE T cells.

CBP binds to the ser133 phosphorylated region of CREB via a domain called KIX (Parker et al., 1996). The phosphorylated domain of CREB was termed KID for kinase-inducible domain. Radhakrishnan et al. (1997) used nuclear magnetic resonance spectroscopy to study the molecular interactions of the KIX:KID domains of CBP and CREB, respectively. The KIX domain of CBP comprises amino acid residues 586 to 666. The KID domain of CREB comprises amino acid residues 101 to 160. The KID undergoes a coil-to-helix folding transition upon binding to KIX, forming 2 alpha helices. The amphipathic helix alpha-B of KID interacts with a hydrophobic groove defined by helices alpha-1 and alpha-3 of KIX. The other KID helix, alpha-A, contacts a different face of the alpha-3 helix. The phosphate group of the critical phosphoserine residue of KID forms a hydrogen bond to the side chain of tyr658 of KIX. The structure provides a model for interactions between other transactivation domains and their targets.

The dominant-negative mutation used by Fentzke et al. (1998) in experiments in transgenic mice (see later) converted ser133 to ala133. The ser133 residue is critical to the positive regulation of the transcriptional activity of CREB by phosphorylation. In the unphosphorylated state, CREB can bind DNA but cannot activate transcription. Phosphorylation of CREB on ser133 facilitates its interaction with the 265-kD CREB-binding domain which in turn is able to interact with and activate the basal transcription complex. The importance of ser133 phosphorylation for CREB transcriptional activity is underscored by the finding that a mutant CREB molecule containing a ser133-to-ala substitution functions as a potent dominant-negative repressor of CREB-dependent gene expression both in vitro and in vivo.

Cocaine causes complex molecular adaptations in brain reward systems, some of which affect its addictive qualities. For example, chronic cocaine use increases formation of cyclic AMP and activity of cAMP-dependent protein kinase (PKA; see 176911) in the nucleus accumbens, a neural substrate for the rewarding actions of cocaine. Increased PKA activity would be suspected to lead to increase phosphorylation of CREB. Carlezon et al. (1998) provided direct evidence for a role of CREB in cocaine actions. Overexpression of CREB in the rat nucleus accumbens, achieved by microinjection of a herpes simplex virus vector (HSV-CREB), decreased the rewarding effects of cocaine and made low doses of the drug aversive. Conversely, overexpression of a dominant-negative mutant CREB increased the rewarding effects of cocaine. Altered transcription of dynorphin (131340) was thought to contribute to these effects.

cAMP mediates the effects of TSH (118850) by regulating thyroid follicular cell proliferation, differentiation, and function. To assess the functional importance of the cAMP response element-binding protein (CREB) in thyroid follicular cell regulation in vivo, Nguyen et al. (2000) targeted the expression of a dominant-negative CREB isoform to the thyroid glands of transgenic mice using a tissue-specific promoter. Transgenic mice exhibited severe growth retardation and primary hypothyroidism. Serum levels of TSH were elevated 8-fold above normal levels, and T4 and T3 levels were low. Ciliated thyroid epithelial cells were observed in the transgenic thyroid glands, suggesting a failure of follicular cell differentiation. Nguyen et al. (2000) concluded that these results demonstrate a critical role for CREB in thyroid growth, differentiation, and function in vivo.

Barco et al. (2002) found that restricted and regulated expression of VP16-CREB, a constitutively active form of CREB, in hippocampal CA1 neurons in mice lowered the threshold for eliciting a persistent late phase of long-term potentiation (LLTP) in the Schaffer collateral pathway. This LLTP had unusual properties in that its induction was not dependent on transcription. Pharmacologic and 2-pathway experiments suggested a model in which VP16-CREB activates the transcription of CRE-driven genes and leads to a cell-wide distribution of proteins that prime the synapses for subsequent synapse-specific capture of LLTP by a weak stimulus. This analysis indicated that synaptic capture of CRE-driven gene products may be sufficient for consolidation of LTP and provided insight into the molecular mechanisms of synaptic tagging and synapse-specific potentiation.

Euskirchen et al. (2004) mapped the distribution of CREB-binding regions along chromosome 22. Chromatin immunoprecipitation of CREB-associated DNA and subsequent hybridization of the associated DNA to a genomic DNA microarray containing all of the nonrepetitive DNA of chromosome 22 revealed 215 binding sites corresponding to 192 different loci and 100 annotated potential gene targets. The authors found binding near or within many genes involved in signal transduction and neuronal function. Only a small fraction of CREB-binding sites were identified near well-defined 5-prime ends of genes. The majority of sites were found elsewhere, including introns and unannotated regions, with several of the latter near transcriptionally active regions. Few CREB targets were identified near full-length canonical CRE sites; the majority contained shorter versions or close matches to this sequence. Several of the CREB targets showed altered expression in human choriocarcinoma cells following forskolin activation, and both induced and repressed genes were found.

Using a combination of in vitro explant assays, mutant analysis, and gene delivery into mouse embryos cultured ex vivo, Chen et al. (2005) demonstrated that adenylyl cyclase (see 103072) signaling through PKA and its target transcription factor CREB are required for Wnt (see 164820)-directed myogenic gene expression. Wnt proteins can also stimulate CREB-mediated transcription, providing evidence for a Wnt signaling pathway involving PKA and CREB.

Various cellular and molecular alterations of the cAMP pathway have been observed in adrenal Cushing syndrome (219080). CREB is the major nuclear target of the cAMP pathway. Rosenberg et al. (2003) analyzed the status of the CREB protein in various types of human adrenocortical tumors and normal fetal adrenal cortex. CREB protein status was studied by Western blot analysis in 27 adrenocortical adenomas and 24 adrenocortical carcinomas. A decrease of CREB protein was seen in the majority of the adrenocortical tumors. The dramatic decrease in CREB protein levels was more pronounced in adrenocortical carcinomas than in adrenocortical adenomas. The secretory status of adenomas was strongly correlated with CREB levels, significantly lower in 9 nonfunctioning adrenocortical adenomas examined than in 9 functioning adrenocortical adenomas. CREB levels, determined by Western blot analysis and immunohistochemistry, were very low in the fetal zone of human fetal adrenal cortex, whereas they were normal in the definitive zone. In tumors, adrenocortical cells in several zones were weakly immunohistochemically stained for CREB, whereas CREB was uniformly detected in nonendocrine cell nuclei. The authors concluded that the absence of CREB may be linked to the development of a highly aggressive tumor with a dedifferentiated benign (nonfunctioning adrenocortical adenoma) or malignant (adrenocortical carcinomas) phenotype.

Dwivedi et al. (2003) studied the characteristics of CREB in suicidal patients because of observations that catalytic properties and/or expression of many kinases that mediate their physiologic responses through the activation of CREB are altered in the postmortem brain of subjects who commit suicide. Brodmann area (BA)-9 and the hippocampus from the brains of 26 suicide subjects and 20 nonpsychiatric healthy control subjects were studied. Messenger RNA levels of CREB and neuron-specific enolase (a control transcript) were determined in total RNA using quantitative RT-PCR. Protein levels and functional characteristics of CREB were determined in nuclear fractions by Western blot analysis and CRE-DNA binding activity, respectively. Catalytic activity of cAMP-stimulated protein kinase A was assayed in nuclear fraction using an enzymatic assay. A significant reduction in mRNA and protein levels of CREB, CRE-DNA binding activity, and basal and cAMP-stimulated protein kinase A activity in BA-9 and hippocampus of suicide subjects was observed. Neuron-specific enolase in BA-9 was unchanged. Except for protein kinase A activity, changes in CREB expression and CRE-DNA binding activity were present in all suicide subjects, regardless of diagnosis. The authors concluded that CREB may play an important role in suicidal behavior.

To examine neuronal competition during memory formation, Han et al. (2007) conducted experiments with mice in which they manipulated the function of CREB in subsets of neurons. Changes in CREB function influenced the probability that individual lateral amygdala neurons were recruited into a fear memory trace. Han et al. (2007) concluded that their results suggest a competitive model underlying memory formation, in which eligible neurons are selected to participate in a memory trace as a function of their relative CREB activity at the time of learning.

Han et al. (2009) used an inducible diphtheria toxin strategy to specifically ablate the CREB-expressing neurons involved in fear memory expression identified by Han et al. (2007). Selectively deleting neurons overexpressing CREB, but not a similar portion of random lateral amygdala neurons, after learning blocked expression of that fear memory. The resulting memory loss was robust and persistent, which suggested that the memory was permanently erased. Han et al. (2009) concluded that their results established a causal link between a specific neuronal subpopulation and memory expression, thereby identifying critical neurons within the memory trace.

Hollander et al. (2010) found that microRNA-212 (MIR212; 613487) was upregulated in the dorsal striatum of rats with a history of extended access to cocaine. Striatal miR212 decreased responsiveness to the motivational properties of cocaine by markedly amplifying the stimulatory effects of the drug on Creb signaling. Studies in rats and HEK cells showed that amplification of CREB signaling occurred through miR212-enhanced RAF1 (164760) activity, resulting in adenylyl cyclase sensitization and increased expression of the essential Creb coactivator TORC (see CRTC1; 607536). miR212 activated RAF1, at least in part, through repression of SPRED1 (609291). Hollander et al. (2010) concluded that striatal miR212 signaling has a key role in determining vulnerability to cocaine addiction.

Mair et al. (2011) showed that both AMPK (see 602739) and calcineurin (see 114105) modulate longevity exclusively through posttranslational modification of CRTC1, the sole C. elegans CRTC. Mair et al. (2011) demonstrated that CRTC1 is a direct AMPK target, and interacts with the CREB homolog-1 (CRH1) transcription factor in vivo. The prolongevity effects of activating AMPK or deactivating calcineurin decrease CRTC1 and CRH1 activity and induce transcriptional responses similar to those of CRH1-null worms. Downregulation of CRTC1 increases life span in a CRH1-dependent manner, and directly reducing CRH1 expression increases longevity, substantiating a role for CRTCs and CREB in aging. Mair et al. (2011) concluded that their findings indicated a novel role for CRTCs and CREB in determining life span downstream of AMPK and calcineurin, and illustrated the molecular mechanisms by which an evolutionarily conserved pathway responds to low energy to increase longevity.

In mice, Seok et al. (2014) showed that Fxr (603826) and the fasting transcriptional activator Creb coordinately regulate the hepatic autophagy gene network. Pharmacologic activation of Fxr repressed many autophagy genes even in the fasted state, and feeding-mediated inhibition of macroautophagy was attenuated in Fxr-knockout mice. From mouse liver chromatin immunoprecipitation and high-throughput sequencing data, Fxr and Creb binding peaks were detected at 178 and 112 genes, respectively, out of 230 autophagy-related genes, and 78 genes showed shared binding, mostly in their promoter regions. Creb promoted autophagic degradation of lipids, or lipophagy, under nutrient-deprived conditions, and Fxr inhibited this response. Mechanistically, Creb upregulated autophagy genes, including Atg7 (608760), Ulk1 (603168), and Tfeb (600744), by recruiting the coactivator Crtc2 (608972). After feeding or pharmacologic activation, Fxr trans-repressed these genes by disrupting the functional Creb-Crtc2 complex. Seok et al. (2014) concluded that their study identified the FXR-CREB axis as a key physiologic switch regulating autophagy, resulting in sustained nutrient regulation of autophagy during feeding/fasting cycles.


▼ Molecular Genetics

Zubenko et al. (2003) detected sequence variations in the promoter and intron 8 of CREB1 that cosegregated with mood disorders, or their absence, in women from 81 families segregating recurrent, early-onset major depressive disorder (see 608516), identifying CREB1 as a likely sex-limited susceptibility gene for unipolar mood disorders, and implicating the cAMP signaling pathway in the pathophysiology of mood disorders and related conditions.

Burcescu et al. (2005) investigated the association of CREB1 with childhood-onset mood disorder in a sample of 195 nuclear families (225 affected children) collected in Hungary and in a sample of 112 probands with mood disorders collected in the Pittsburgh area and matching controls. Genotyping for 2 DNA variants previously found to be associated, -656G/A and a C ins/del in intron 8, as well as for 3 additional polymorphisms spanning CREB1, revealed no evidence for association with early-onset mood disorder or for a sex-specific relationship.

In tumor tissue samples from unrelated 8 patients with angiomatoid fibrous histiocytoma (612160), Antonescu et al. (2007) identified an identical EWSR1 (133450)/CREB1 fusion transcript with exon 7 of EWSR1 fused to exon 7 of CREB1. The authors concluded that this fusion gene is the most common genetic abnormality in this tumor type.


▼ Animal Model

Bourtchuladze et al. (1994) found that mice lacking expression of the alpha and delta isoforms of Creb were profoundly deficient in long-term memory, but not short-term memory. Electrophysiologic studies in hippocampal slices revealed that long-term potentiation in Creb mutants was small and decayed rapidly compared with wildtype. Paired-pulse facilitation and posttetanic potentiation appeared normal.

Fentzke et al. (1998) found that transgenic mice expressing a dominant-negative form of the CREB transcription factor under the control of the cardiac myocyte-specific alpha-myosin heavy chain promoter (MYH6; 160710) developed dilated cardiomyopathy that closely resembled human idiopathic dilated cardiomyopathy in many of its anatomic, physiologic, and clinical features. Between 2 and 20 weeks of age, these mice developed 4 chamber cardiac dilatation, decreased systolic and diastolic left ventricular function, and attenuated contractile responses to the beta-adrenergic agonist, isoproterenol. The authors thought the results indicated that CREB is an important regulator of cardiac myocyte function and provided a genetic model of dilated cardiomyopathy that should facilitate studies of both the pathogenesis and therapy of the clinical disorder.

Rudolph et al. (1998) generated Creb-null mice that had all functional isoforms of the gene (alpha, beta, and delta) inactivated. The Creb-null mice were smaller than their littermates and died immediately after birth from respiratory distress. The brains of the null mice showed a strong reduction in the corpus callosum and the anterior commissures. The mice also showed impaired fetal T-cell development of the alpha-beta lineage. Overall thymic cellularity in the null mice was severely reduced, affecting all developmental stages of the alpha-beta T-cell lineage.

Herzig et al. (2001) demonstrated that mice carrying a targeted disruption of the CREB protein gene, or overexpressing a dominant-negative CREB inhibitor, exhibit fasting hypoglycemia and reduced expression of gluconeogenic enzymes. CREB induces expression of the gluconeogenic program through the nuclear receptor coactivator PGC1 (604517), which was demonstrated to be a direct target for CREB regulation in vivo. Overexpression of PGC1 in CREB-deficient mice restored glucose homeostasis and rescued the expression of gluconeogenic genes. In transient assays, PGC1 potentiated glucocorticoid induction of the gene for PEPCK (614168), the rate-limiting enzyme in gluconeogenesis. PGC1 promotes cooperation between cAMP and glucocorticoid signaling pathways during hepatic gluconeogenesis. Fasting hyperglycemia is strongly correlated with type II diabetes (125853), so Herzig et al. (2001) concluded that the activation of PGC1 by CREB in liver contributes importantly to the pathogenesis of this disease.

Pittenger et al. (2002) interfered with the normal function of CREB family transcription factors in the dorsal hippocampus of transgenic mice expressing a mutant of human CREB, called KCREB (Walton et al., 1992), that is a dominant-negative inhibitor of the CREB family transcription factors CREB, CREM, and ATF1 (123803). Pittenger et al. (2002) observed that their KCREB transgenic animals were impaired in the Morris water maze test, which specifically requires the dorsal hippocampus. Results of an object recognition task showed that the deficit was specific to long-term memory. Several forms of LLTP were normal, but forskolin-induced and dopamine-regulated potentiation were disrupted. Pittenger et al. (2002) concluded that CREB has a role in hippocampus-dependent learning.

Kida et al. (2002) generated transgenic mice with an inducible and reversible CREB repressor by fusing CREB with a ser133-to-ala mutation to a tamoxifen-dependent mutant of an estrogen receptor ligand-binding domain. They found that CREB is crucial for the consolidation of long-term conditioned fear memories, but not for encoding, storage, or retrieval of these memories. Their studies also showed that CREB is required for the stability of reactivated or retrieved conditioned fear memories. Although the transcriptional processes necessary for the stability of initial and reactivated memories differ, CREB was found to be required for both.

Activation of CREB by phosphorylation has been implicated in the survival of mammalian cells. To define its roles in the mouse central nervous system, Mantamadiotis et al. (2002) disrupted Creb1 in brain of developing and adult mice using the Cre/loxP system. They found that mice with a genome background in which the cAMP response element modulator (CREM; 123812) had been knocked out and who also lacked Creb in the central nervous system during development showed extensive apoptosis of postmitotic neurons. By contrast, mice in which both Creb1 and Crem were disrupted in the postnatal forebrain showed progressive neurodegeneration in the hippocampus and in the dorsolateral striatum. The striatal phenotype was reminiscent of Huntington disease (143100) and consistent with the postulated role of CREB-mediated signaling in polyglutamine-triggered diseases.

By analyzing the Creb knockout mice generated by Rudolph et al. (1998), Lonze et al. (2002) concluded that CREB is critical for several aspects of neuronal development. Creb-null mice exhibited excess apoptosis, degeneration of sensory neurons, and impaired axonal growth and projections. They concluded that CREB is required within sensory and sympathetic neurons for survival and axon extension because both of these neurotrophin-dependent processes were compromised in cultured neurons from the Creb-null mice. The authors hypothesized that CREB is a key nuclear target of neurotrophin-stimulated cellular events that are critical for the survival of peripheral neurons and for the proper establishment of the peripheral nervous system.

Herzig et al. (2003) generated mice infected with dominant-negative Creb-expressing adenovirus and showed that, compared with control littermates, the Creb-deficient mice had a fatty liver phenotype and a pronounced increase in hepatic triglyceride content and in plasma triglyceride levels on a high-fat diet. The heterozygotes also displayed higher liver triglyceride contents than wildtype littermates. Creb-deficient mice displayed elevated expression of the nuclear hormone receptor Ppar-gamma (601487). CREB inhibits hepatic PPAR-gamma expression in the fasted state by stimulating the expression of the hairy/enhancer of split (HES1; 139605) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo. Herzig et al. (2003) concluded that the coordinate induction of PGC1 and repression of PPAR-gamma by CREB during fasting provides a molecular rationale for the antagonism between insulin and counter-regulatory hormones, and indicates a potential role for CREB antagonists as therapeutic agents in enhancing insulin sensitivity in the liver.

Berdeaux et al. (2007) found that transgenic mice expressing a dominant-negative form of Creb (A-Creb) in muscle exhibited a dystrophic phenotype accompanied by extensive fiber necrosis and reduced Mef2 (see 600660) activity. Class II HDAC (see HDAC5; 605315) phosphorylation was decreased in A-Creb myofibers due to a reduction in the levels of Sik1 (SNF1LK; 605705), a Creb target gene that functions as a class II HDAC kinase. Inhibition of class II HDAC activity via expression of Sik1 or a small molecule inhibitor ameliorated the dystrophic phenotype of mice expressing A-Creb in muscle, suggesting that the SIK1-HDAC pathway has a role in regulating muscle function.


▼ ALLELIC VARIANTS ( 1 Selected Example):

.0001 VARIANT OF UNKNOWN SIGNIFICANCE

CREB1, ASP116GLY
  
RCV000022519

This variant is classified as a variant of unknown significance because its contribution to a lethal multiple malformation syndrome has not been confirmed.

By targeted sequencing of the CREB1 gene in a newborn with multiple congenital anomalies, Kitazawa et al. (2012) identified a de novo heterozygous 347A-G transition in the CREB1 gene, resulting in an asp116-to-gly (D116G) substitution in the kinase-inducible domain (KID) of the protein. The CREB1 gene was chosen for sequencing because the phenotype closely resembled that of Creb-null mice (Rudolph et al., 1998). The patient was born with agenesis of the corpus callosum, cerebellar hypoplasia, severe neonatal respiratory distress refractory to surfactant, thymus hypoplasia, and thyroid follicular hypoplasia, and died at age 26 weeks. In vitro functional expression studies in HEK293 cells showed that the mutant D116G protein had an inhibitory effect on transcriptional activity. Although the mutant protein was phosphorylated at ser133 after forskolin treatment, it failed to associate with transcriptional coactivators CREBBP (600140) and EP300 (602700), suggesting that the mutant protein had an altered 3-dimensional structure. The mutant protein blocked the transactivation of target genes in a dominant-negative manner. Kitazawa et al. (2012) noted that the protein kinase A/CREBBP/EP300 pathway is also impaired in Rubinstein-Taybi syndrome (see RSTS1, 180849).


▼ REFERENCES

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  20. Hollander, J. A., Im, H.-I., Amelio, A. L., Kocerha, J., Bali, P., Lu, Q., Willoughby, D., Wahlestedt, C., Conkright, M. D., Kenny, P. J. Striatal microRNA controls cocaine intake through CREB signalling. Nature 466: 197-202, 2010. [PubMed: 20613834, images, related citations] [Full Text]

  21. Kida, S., Josselyn, S. A., Pena de Ortiz, S., Kogan, J. H., Chevere, I., Masushige, S., Silva, A. J. CREB required for the stability of new and reactivated fear memories. Nature Neurosci. 5: 348-355, 2002. [PubMed: 11889468, related citations] [Full Text]

  22. Kitazawa, S., Kondo, T., Mori, K., Yokoyama, N., Matsuo, M., Kitazawa, R. A p.D116G mutation in CREB1 leads to novel multiple malformation syndrome resembling CrebA knockout mouse. Hum. Mutat. 33: 651-654, 2012. [PubMed: 22267179, related citations] [Full Text]

  23. Lonze, B. E., Riccio, A., Cohen, S., Ginty, D. D. Apoptosis, axonal growth defects, and degeneration of peripheral neurons in mice lacking CREB. Neuron 34: 371-385, 2002. [PubMed: 11988169, related citations] [Full Text]

  24. Mair, W., Morantte, I., Rodrigues, A. P. C., Manning, G., Montminy, M., Shaw, R. J., Dillin, A. Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature 470: 404-408, 2011. [PubMed: 21331044, images, related citations] [Full Text]

  25. Mantamadiotis, T., Lemberger, T., Bleckmann, S. C., Kern, H., Kretz, O., Villalba, A. M., Tronche, F., Kellendonk, C., Gau, D., Kapfhammer, J., Otto, C., Schmid, W., Schutz, G. Disruption of CREB function in brain leads to neurodegeneration. Nature Genet. 31: 47-54, 2002. [PubMed: 11967539, related citations] [Full Text]

  26. Montminy, M. R., Bilezikjian, L. M. Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene. Nature 328: 175-178, 1987. [PubMed: 2885756, related citations] [Full Text]

  27. Montminy, M. R., Sevarino, K. A., Wagner, J. A., Mandel, G., Goodman, R. H. Identification of a cyclic-AMP-responsive element within the rat somatostatin gene. Proc. Nat. Acad. Sci. 83: 6682-6686, 1986. [PubMed: 2875459, related citations] [Full Text]

  28. Nguyen, L. Q., Kopp, P., Martinson, F., Stanfield, K., Roth, S. I., Jameson, J. L. A dominant negative CREB (cAMP response element-binding protein) isoform inhibits thyrocyte growth, thyroid-specific gene expression, differentiation, and function. Molec. Endocr. 14: 1448-1461, 2000. [PubMed: 10976922, related citations] [Full Text]

  29. Parker, D., Ferreri, K., Nakajima, T., LaMorte, V. J., Evans, R., Koerber, S. C., Hoeger, C., Montminy, M. R. Phosphorylation of CREB at ser-133 induces complex formation with CREB-binding protein via a direct mechanism. Molec. Cell. Biol. 16: 694-703, 1996. [PubMed: 8552098, related citations] [Full Text]

  30. Pittenger, C., Huang, Y. Y., Paletzki, R. F., Bourtchouladze, R., Scanlin, H., Vronskaya, S., Kandel, E. R. Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory. Neuron 34: 447-462, 2002. [PubMed: 11988175, related citations] [Full Text]

  31. Radhakrishnan, I., Perez-Alvarado, G. C., Parker, D., Dyson, H. J., Montminy, M. R., Wright, P. E. Solution structure of the KIX domain of CBP bound to the transactivation domain of CREB: a model for activator:coactivator interactions. Cell 91: 741-752, 1997. [PubMed: 9413984, related citations] [Full Text]

  32. Rosenberg, D., Groussin, L., Jullian, E., Perlemoine, K., Medjane, S., Louvel, A., Bertagna, X., Bertherat, J. Transcription factor 3-prime,5-prime-cyclic adenosine 5-prime-monophosphate-responsive element-binding protein (CREB) is decreased during human adrenal cortex tumorigenesis and fetal development. J. Clin. Endocr. Metab. 88: 3958-3965, 2003. [PubMed: 12915693, related citations] [Full Text]

  33. Rudolph, D., Tafuri, A., Gass, P., Hammerling, G. J., Arnold, B., Schutz, G. Impaired fetal T cell development and perinatal lethality in mice lacking the cAMP response element binding protein. Proc. Nat. Acad. Sci. 95: 4481-4486, 1998. [PubMed: 9539763, images, related citations] [Full Text]

  34. Ruppert, S., Cole, T. J., Boshart, M., Schmid, E., Schutz, G. Multiple mRNA isoforms of the transcription activator protein CREB: generation by alternative splicing and specific expression in primary spermatocytes. EMBO J. 11: 1503-1512, 1992. [PubMed: 1532935, related citations] [Full Text]

  35. Seok, S., Fu, T., Choi, S.-E., Li, Y., Zhu, R., Kumar, S., Sun, X., Yoon, G., Kang, Y., Zhong, W., Ma, J., Kemper, B., Kemper, J. K. Transcriptional regulation of autophagy by an FXR-CREB axis. Nature 516: 108-111, 2014. [PubMed: 25383523, images, related citations] [Full Text]

  36. Solomou, E. E., Juang, Y.-T., Gourley, M. F., Kammer, G. M., Tsokos, G. C. Molecular basis of deficient IL-2 production in T cells from patients with systemic lupus erythematosus. J. Immun. 166: 4216-4222, 2001. [PubMed: 11238674, related citations] [Full Text]

  37. Taylor, A. K., Klisak, I., Mohandas, T., Sparkes, R. S., Li, C., Gaynor, R., Lusis, A. J. Assignment of the human gene for CREB1 to chromosome 2q32.3-q34. Genomics 7: 416-421, 1990. [PubMed: 2142119, related citations] [Full Text]

  38. Walton, K. M., Rehfuss, R. P., Chrivia, J. C., Lochner, J. E., Goodman, R. H. A dominant repressor of cyclic adenosine 3-prime,5-prime-monophosphate (cAMP)-regulated enhancer-binding protein activity inhibits the cAMP-mediated induction of the somatostatin promoter in vivo. Molec. Endocr. 6: 647-655, 1992. [PubMed: 1350057, related citations] [Full Text]

  39. Zubenko, G. S., Hughes, H. B., III, Stiffler, J. S., Brechbiel, A., Zubenko, W. N., Maher, B. S., Marazita, M. L. Sequence variations in CREB1 cosegregate with depressive disorders in women. Molec. Psychiat. 8: 611-618, 2003. [PubMed: 12851637, related citations] [Full Text]


Contributors:
Patricia A. Hartz - updated : 10/19/2017
Ada Hamosh - updated : 01/15/2015
Cassandra L. Kniffin - updated : 4/16/2012
Ada Hamosh - updated : 6/29/2011
Ada Hamosh - updated : 8/24/2010
Ada Hamosh - updated : 4/7/2009
Cassandra L. Kniffin - updated : 7/3/2008
Paul J. Converse - updated : 10/11/2007
Ada Hamosh - updated : 5/30/2007
John Logan Black, III - updated : 8/22/2006
John Logan Black, III - updated : 6/9/2005
Ada Hamosh - updated : 2/25/2005
Patricia A. Hartz - updated : 6/25/2004
John A. Phillips, III - updated : 2/10/2004
Ada Hamosh - updated : 12/3/2003
John Logan Black, III - updated : 7/17/2003
Dawn Watkins-Chow - updated : 5/20/2003
Dawn Watkins-Chow - updated : 12/17/2002
John A. Phillips, III - updated : 7/23/2002
Victor A. McKusick - updated : 5/6/2002
Ada Hamosh - updated : 3/28/2002
Stylianos E. Antonarakis - updated : 3/25/2002
Ada Hamosh - updated : 9/12/2001
Paul J. Converse - updated : 4/27/2001
Victor A. McKusick - updated : 12/17/1998
Victor A. McKusick - updated : 6/26/1998
Stylianos E. Antonarakis - updated : 1/23/1998
Creation Date:
Victor A. McKusick : 7/5/1990
Edit History:
alopez : 06/13/2022
carol : 10/20/2017
mgross : 10/19/2017
alopez : 01/15/2015
carol : 7/8/2014
carol : 11/2/2012
carol : 6/5/2012
alopez : 4/20/2012
ckniffin : 4/16/2012
carol : 11/22/2011
alopez : 7/5/2011
alopez : 7/5/2011
terry : 6/29/2011
terry : 5/17/2011
mgross : 8/25/2010
terry : 8/24/2010
alopez : 4/8/2009
terry : 4/7/2009
wwang : 7/8/2008
ckniffin : 7/3/2008
mgross : 10/11/2007
alopez : 6/14/2007
terry : 5/30/2007
carol : 8/22/2006
carol : 6/9/2005
terry : 3/14/2005
carol : 3/9/2005
wwang : 3/9/2005
wwang : 3/2/2005
terry : 2/25/2005
mgross : 6/30/2004
terry : 6/25/2004
alopez : 2/10/2004
tkritzer : 2/3/2004
alopez : 12/4/2003
alopez : 12/4/2003
terry : 12/3/2003
terry : 8/15/2003
carol : 7/21/2003
terry : 7/17/2003
carol : 5/20/2003
carol : 2/4/2003
tkritzer : 12/17/2002
tkritzer : 12/17/2002
tkritzer : 7/23/2002
alopez : 5/6/2002
alopez : 5/6/2002
alopez : 4/12/2002
mgross : 3/29/2002
terry : 3/28/2002
mgross : 3/25/2002
terry : 11/15/2001
carol : 11/7/2001
alopez : 9/12/2001
terry : 9/12/2001
mgross : 4/27/2001
mgross : 4/27/2001
alopez : 8/28/2000
alopez : 12/17/1998
dkim : 10/20/1998
carol : 6/30/1998
dkim : 6/30/1998
terry : 6/26/1998
terry : 6/26/1998
carol : 1/26/1998
carol : 1/23/1998
mark : 2/15/1996
mark : 2/8/1996
carol : 11/5/1992
carol : 8/13/1992
supermim : 3/16/1992
carol : 2/28/1992
carol : 7/5/1990

* 123810

cAMP RESPONSE ELEMENT-BINDING PROTEIN 1; CREB1


Alternative titles; symbols

CREB


Other entities represented in this entry:

CREB/EWS FUSION GENE, INCLUDED

HGNC Approved Gene Symbol: CREB1

Cytogenetic location: 2q33.3     Genomic coordinates (GRCh38): 2:207,529,962-207,605,988 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number 		Inheritance Phenotype
mapping key
2q33.3 Histiocytoma, angiomatoid fibrous, somatic 612160 3

TEXT

Cloning and Expression

Cyclic AMP (cAMP) second messenger pathways provide a chief means by which cellular growth, differentiation, and function can be influenced by extracellular signals. Following hormonal stimulation of a neuroendocrine cell, for example, increased cAMP levels activate cAMP-dependent protein kinase A, which phosphorylates 1 or more DNA-binding proteins. These in turn stimulate transcription of an array of cAMP-responsive genes such as those for somatostatin (182450), alpha-gonadotropin (118850), proenkephalin (131330) and FOS (164810). All cAMP-responsive gene promoters have in common an 8-base enhancer known as the cAMP-response element (CRE) containing a conserved core sequence, 5-prime-TGACG-3-prime, first described in the somatostatin gene by Montminy et al. (1986). Montminy and Bilezikjian (1987) purified a 43-kD nuclear phosphoprotein that bound to CRE with high affinity.

Hoeffler et al. (1988) isolated cDNA clones for human CREB. The deduced 326-amino acid protein has an N-terminal acidic region, a leucine zipper-like sequence, and a C-terminal basic region. The acidic region may be a transcriptional activation domain, and the leucine zipper may bind DNA or DNA-associated proteins.

By PCR of a human peripheral blood T-cell cDNA library, Berkowitz and Gilman (1990) identified 2 variants of CREB1, which they called CREB-A and CREB-B. CREB-A is identical to the CREB variant cloned by Hoeffler et al. (1988). CREB-B encodes a deduced 341-amino acid protein containing a 14-amino acid serine-rich insertion at amino acid 88 of CREB-A. RNase protection assays detected both transcripts in several human cell lines and in rodent cell lines and tissues.

Ruppert et al. (1992) cloned several splice variants of mouse Creb that appeared to have protein-coding potential. The longest isoform, Creb-alpha, contains 341 amino acids, and the most common isoform, Creb-delta, lacks 14 amino acids near the N terminus.


Mapping

By use of a cDNA probe for Southern blot analysis of genomic DNA from a panel of mouse/human somatic cell hybrids and for in situ hybridization, Taylor et al. (1990) mapped CREB1 to 2q32.3-q34. Taylor et al. (1990) speculated about the possible involvement of CREB1 in genetic disorders or cancer and pointed to the fact that TCL4 (186860), a locus implicated in T-cell leukemia/lymphoma, is located at 2q34. Cole et al. (1992) demonstrated that the Creb1 locus maps to the proximal region of mouse chromosome 1. The CREB gene was found to be single copy in the mouse and well conserved through evolution. Barton et al. (1992) mapped the Creb1 gene to mouse chromosome 1 by linkage studies. It was found to be approximately 1 cM distal to Cryg and 7 cM proximal to Vil.


Gene Function

Using an in vitro binding assay, Berkowitz and Gilman (1990) found that both CREB-A and CREB-B specifically bound a cAMP response element. Both bound DNA as dimers and imparted cAMP-regulated transcriptional activity to a heterologous DNA-binding domain. The authors concluded that the 2 isoforms may regulate distinct gene activities.

Transcriptional activity of CREB requires phosphorylation of the protein on a serine residue at position 119. The CRE element (TGANNTCA) to which CREB binds is present in a number of T-cell genes, but the precise role of CREB in T-cell differentiation and function had been unknown. Barton et al. (1996) showed that resting thymocytes contain predominantly unphosphorylated (i.e., inactive) CREB, which is rapidly activated by phosphorylation on ser119 following thymocyte activation. T-cell development is normal in transgenic mice that express a dominant-negative form of CREB (with alanine at position 119) under the control of a T-cell-specific CD2 promoter/enhancer. In contrast, thymocytes and T cells from these animals display a profound proliferative defect characterized by markedly decreased interleukin-2 (IL2; 147680) production, G1 cell cycle arrest, and subsequent apoptotic death in response to a number of different activation signals. Barton et al. (1996) proposed that T-cell activation leads to the phosphorylation and activation of CREB, which in turn is required for the normal induction of the transcription factor AP1 (see 165160) and subsequent interleukin-2 production and cell cycle progression.

Using EMSA analysis, Solomou et al. (2001) showed that while stimulated T cells from normal individuals had increased binding of phosphorylated CREB to the -180 site of the IL2 promoter, nearly all stimulated T cells from systemic lupus erythematosus (SLE; 152700) patients had increased binding primarily of phosphorylated CREM (123812) at this site and to the transcriptional coactivators CREBBP (600140) and EP300 (602700). Increased expression of phosphorylated CREM correlated with decreased production of IL2. Solomou et al. (2001) concluded that transcriptional repression is responsible for the decreased production of IL2 and anergy in SLE T cells.

CBP binds to the ser133 phosphorylated region of CREB via a domain called KIX (Parker et al., 1996). The phosphorylated domain of CREB was termed KID for kinase-inducible domain. Radhakrishnan et al. (1997) used nuclear magnetic resonance spectroscopy to study the molecular interactions of the KIX:KID domains of CBP and CREB, respectively. The KIX domain of CBP comprises amino acid residues 586 to 666. The KID domain of CREB comprises amino acid residues 101 to 160. The KID undergoes a coil-to-helix folding transition upon binding to KIX, forming 2 alpha helices. The amphipathic helix alpha-B of KID interacts with a hydrophobic groove defined by helices alpha-1 and alpha-3 of KIX. The other KID helix, alpha-A, contacts a different face of the alpha-3 helix. The phosphate group of the critical phosphoserine residue of KID forms a hydrogen bond to the side chain of tyr658 of KIX. The structure provides a model for interactions between other transactivation domains and their targets.

The dominant-negative mutation used by Fentzke et al. (1998) in experiments in transgenic mice (see later) converted ser133 to ala133. The ser133 residue is critical to the positive regulation of the transcriptional activity of CREB by phosphorylation. In the unphosphorylated state, CREB can bind DNA but cannot activate transcription. Phosphorylation of CREB on ser133 facilitates its interaction with the 265-kD CREB-binding domain which in turn is able to interact with and activate the basal transcription complex. The importance of ser133 phosphorylation for CREB transcriptional activity is underscored by the finding that a mutant CREB molecule containing a ser133-to-ala substitution functions as a potent dominant-negative repressor of CREB-dependent gene expression both in vitro and in vivo.

Cocaine causes complex molecular adaptations in brain reward systems, some of which affect its addictive qualities. For example, chronic cocaine use increases formation of cyclic AMP and activity of cAMP-dependent protein kinase (PKA; see 176911) in the nucleus accumbens, a neural substrate for the rewarding actions of cocaine. Increased PKA activity would be suspected to lead to increase phosphorylation of CREB. Carlezon et al. (1998) provided direct evidence for a role of CREB in cocaine actions. Overexpression of CREB in the rat nucleus accumbens, achieved by microinjection of a herpes simplex virus vector (HSV-CREB), decreased the rewarding effects of cocaine and made low doses of the drug aversive. Conversely, overexpression of a dominant-negative mutant CREB increased the rewarding effects of cocaine. Altered transcription of dynorphin (131340) was thought to contribute to these effects.

cAMP mediates the effects of TSH (118850) by regulating thyroid follicular cell proliferation, differentiation, and function. To assess the functional importance of the cAMP response element-binding protein (CREB) in thyroid follicular cell regulation in vivo, Nguyen et al. (2000) targeted the expression of a dominant-negative CREB isoform to the thyroid glands of transgenic mice using a tissue-specific promoter. Transgenic mice exhibited severe growth retardation and primary hypothyroidism. Serum levels of TSH were elevated 8-fold above normal levels, and T4 and T3 levels were low. Ciliated thyroid epithelial cells were observed in the transgenic thyroid glands, suggesting a failure of follicular cell differentiation. Nguyen et al. (2000) concluded that these results demonstrate a critical role for CREB in thyroid growth, differentiation, and function in vivo.

Barco et al. (2002) found that restricted and regulated expression of VP16-CREB, a constitutively active form of CREB, in hippocampal CA1 neurons in mice lowered the threshold for eliciting a persistent late phase of long-term potentiation (LLTP) in the Schaffer collateral pathway. This LLTP had unusual properties in that its induction was not dependent on transcription. Pharmacologic and 2-pathway experiments suggested a model in which VP16-CREB activates the transcription of CRE-driven genes and leads to a cell-wide distribution of proteins that prime the synapses for subsequent synapse-specific capture of LLTP by a weak stimulus. This analysis indicated that synaptic capture of CRE-driven gene products may be sufficient for consolidation of LTP and provided insight into the molecular mechanisms of synaptic tagging and synapse-specific potentiation.

Euskirchen et al. (2004) mapped the distribution of CREB-binding regions along chromosome 22. Chromatin immunoprecipitation of CREB-associated DNA and subsequent hybridization of the associated DNA to a genomic DNA microarray containing all of the nonrepetitive DNA of chromosome 22 revealed 215 binding sites corresponding to 192 different loci and 100 annotated potential gene targets. The authors found binding near or within many genes involved in signal transduction and neuronal function. Only a small fraction of CREB-binding sites were identified near well-defined 5-prime ends of genes. The majority of sites were found elsewhere, including introns and unannotated regions, with several of the latter near transcriptionally active regions. Few CREB targets were identified near full-length canonical CRE sites; the majority contained shorter versions or close matches to this sequence. Several of the CREB targets showed altered expression in human choriocarcinoma cells following forskolin activation, and both induced and repressed genes were found.

Using a combination of in vitro explant assays, mutant analysis, and gene delivery into mouse embryos cultured ex vivo, Chen et al. (2005) demonstrated that adenylyl cyclase (see 103072) signaling through PKA and its target transcription factor CREB are required for Wnt (see 164820)-directed myogenic gene expression. Wnt proteins can also stimulate CREB-mediated transcription, providing evidence for a Wnt signaling pathway involving PKA and CREB.

Various cellular and molecular alterations of the cAMP pathway have been observed in adrenal Cushing syndrome (219080). CREB is the major nuclear target of the cAMP pathway. Rosenberg et al. (2003) analyzed the status of the CREB protein in various types of human adrenocortical tumors and normal fetal adrenal cortex. CREB protein status was studied by Western blot analysis in 27 adrenocortical adenomas and 24 adrenocortical carcinomas. A decrease of CREB protein was seen in the majority of the adrenocortical tumors. The dramatic decrease in CREB protein levels was more pronounced in adrenocortical carcinomas than in adrenocortical adenomas. The secretory status of adenomas was strongly correlated with CREB levels, significantly lower in 9 nonfunctioning adrenocortical adenomas examined than in 9 functioning adrenocortical adenomas. CREB levels, determined by Western blot analysis and immunohistochemistry, were very low in the fetal zone of human fetal adrenal cortex, whereas they were normal in the definitive zone. In tumors, adrenocortical cells in several zones were weakly immunohistochemically stained for CREB, whereas CREB was uniformly detected in nonendocrine cell nuclei. The authors concluded that the absence of CREB may be linked to the development of a highly aggressive tumor with a dedifferentiated benign (nonfunctioning adrenocortical adenoma) or malignant (adrenocortical carcinomas) phenotype.

Dwivedi et al. (2003) studied the characteristics of CREB in suicidal patients because of observations that catalytic properties and/or expression of many kinases that mediate their physiologic responses through the activation of CREB are altered in the postmortem brain of subjects who commit suicide. Brodmann area (BA)-9 and the hippocampus from the brains of 26 suicide subjects and 20 nonpsychiatric healthy control subjects were studied. Messenger RNA levels of CREB and neuron-specific enolase (a control transcript) were determined in total RNA using quantitative RT-PCR. Protein levels and functional characteristics of CREB were determined in nuclear fractions by Western blot analysis and CRE-DNA binding activity, respectively. Catalytic activity of cAMP-stimulated protein kinase A was assayed in nuclear fraction using an enzymatic assay. A significant reduction in mRNA and protein levels of CREB, CRE-DNA binding activity, and basal and cAMP-stimulated protein kinase A activity in BA-9 and hippocampus of suicide subjects was observed. Neuron-specific enolase in BA-9 was unchanged. Except for protein kinase A activity, changes in CREB expression and CRE-DNA binding activity were present in all suicide subjects, regardless of diagnosis. The authors concluded that CREB may play an important role in suicidal behavior.

To examine neuronal competition during memory formation, Han et al. (2007) conducted experiments with mice in which they manipulated the function of CREB in subsets of neurons. Changes in CREB function influenced the probability that individual lateral amygdala neurons were recruited into a fear memory trace. Han et al. (2007) concluded that their results suggest a competitive model underlying memory formation, in which eligible neurons are selected to participate in a memory trace as a function of their relative CREB activity at the time of learning.

Han et al. (2009) used an inducible diphtheria toxin strategy to specifically ablate the CREB-expressing neurons involved in fear memory expression identified by Han et al. (2007). Selectively deleting neurons overexpressing CREB, but not a similar portion of random lateral amygdala neurons, after learning blocked expression of that fear memory. The resulting memory loss was robust and persistent, which suggested that the memory was permanently erased. Han et al. (2009) concluded that their results established a causal link between a specific neuronal subpopulation and memory expression, thereby identifying critical neurons within the memory trace.

Hollander et al. (2010) found that microRNA-212 (MIR212; 613487) was upregulated in the dorsal striatum of rats with a history of extended access to cocaine. Striatal miR212 decreased responsiveness to the motivational properties of cocaine by markedly amplifying the stimulatory effects of the drug on Creb signaling. Studies in rats and HEK cells showed that amplification of CREB signaling occurred through miR212-enhanced RAF1 (164760) activity, resulting in adenylyl cyclase sensitization and increased expression of the essential Creb coactivator TORC (see CRTC1; 607536). miR212 activated RAF1, at least in part, through repression of SPRED1 (609291). Hollander et al. (2010) concluded that striatal miR212 signaling has a key role in determining vulnerability to cocaine addiction.

Mair et al. (2011) showed that both AMPK (see 602739) and calcineurin (see 114105) modulate longevity exclusively through posttranslational modification of CRTC1, the sole C. elegans CRTC. Mair et al. (2011) demonstrated that CRTC1 is a direct AMPK target, and interacts with the CREB homolog-1 (CRH1) transcription factor in vivo. The prolongevity effects of activating AMPK or deactivating calcineurin decrease CRTC1 and CRH1 activity and induce transcriptional responses similar to those of CRH1-null worms. Downregulation of CRTC1 increases life span in a CRH1-dependent manner, and directly reducing CRH1 expression increases longevity, substantiating a role for CRTCs and CREB in aging. Mair et al. (2011) concluded that their findings indicated a novel role for CRTCs and CREB in determining life span downstream of AMPK and calcineurin, and illustrated the molecular mechanisms by which an evolutionarily conserved pathway responds to low energy to increase longevity.

In mice, Seok et al. (2014) showed that Fxr (603826) and the fasting transcriptional activator Creb coordinately regulate the hepatic autophagy gene network. Pharmacologic activation of Fxr repressed many autophagy genes even in the fasted state, and feeding-mediated inhibition of macroautophagy was attenuated in Fxr-knockout mice. From mouse liver chromatin immunoprecipitation and high-throughput sequencing data, Fxr and Creb binding peaks were detected at 178 and 112 genes, respectively, out of 230 autophagy-related genes, and 78 genes showed shared binding, mostly in their promoter regions. Creb promoted autophagic degradation of lipids, or lipophagy, under nutrient-deprived conditions, and Fxr inhibited this response. Mechanistically, Creb upregulated autophagy genes, including Atg7 (608760), Ulk1 (603168), and Tfeb (600744), by recruiting the coactivator Crtc2 (608972). After feeding or pharmacologic activation, Fxr trans-repressed these genes by disrupting the functional Creb-Crtc2 complex. Seok et al. (2014) concluded that their study identified the FXR-CREB axis as a key physiologic switch regulating autophagy, resulting in sustained nutrient regulation of autophagy during feeding/fasting cycles.


Molecular Genetics

Zubenko et al. (2003) detected sequence variations in the promoter and intron 8 of CREB1 that cosegregated with mood disorders, or their absence, in women from 81 families segregating recurrent, early-onset major depressive disorder (see 608516), identifying CREB1 as a likely sex-limited susceptibility gene for unipolar mood disorders, and implicating the cAMP signaling pathway in the pathophysiology of mood disorders and related conditions.

Burcescu et al. (2005) investigated the association of CREB1 with childhood-onset mood disorder in a sample of 195 nuclear families (225 affected children) collected in Hungary and in a sample of 112 probands with mood disorders collected in the Pittsburgh area and matching controls. Genotyping for 2 DNA variants previously found to be associated, -656G/A and a C ins/del in intron 8, as well as for 3 additional polymorphisms spanning CREB1, revealed no evidence for association with early-onset mood disorder or for a sex-specific relationship.

In tumor tissue samples from unrelated 8 patients with angiomatoid fibrous histiocytoma (612160), Antonescu et al. (2007) identified an identical EWSR1 (133450)/CREB1 fusion transcript with exon 7 of EWSR1 fused to exon 7 of CREB1. The authors concluded that this fusion gene is the most common genetic abnormality in this tumor type.


Animal Model

Bourtchuladze et al. (1994) found that mice lacking expression of the alpha and delta isoforms of Creb were profoundly deficient in long-term memory, but not short-term memory. Electrophysiologic studies in hippocampal slices revealed that long-term potentiation in Creb mutants was small and decayed rapidly compared with wildtype. Paired-pulse facilitation and posttetanic potentiation appeared normal.

Fentzke et al. (1998) found that transgenic mice expressing a dominant-negative form of the CREB transcription factor under the control of the cardiac myocyte-specific alpha-myosin heavy chain promoter (MYH6; 160710) developed dilated cardiomyopathy that closely resembled human idiopathic dilated cardiomyopathy in many of its anatomic, physiologic, and clinical features. Between 2 and 20 weeks of age, these mice developed 4 chamber cardiac dilatation, decreased systolic and diastolic left ventricular function, and attenuated contractile responses to the beta-adrenergic agonist, isoproterenol. The authors thought the results indicated that CREB is an important regulator of cardiac myocyte function and provided a genetic model of dilated cardiomyopathy that should facilitate studies of both the pathogenesis and therapy of the clinical disorder.

Rudolph et al. (1998) generated Creb-null mice that had all functional isoforms of the gene (alpha, beta, and delta) inactivated. The Creb-null mice were smaller than their littermates and died immediately after birth from respiratory distress. The brains of the null mice showed a strong reduction in the corpus callosum and the anterior commissures. The mice also showed impaired fetal T-cell development of the alpha-beta lineage. Overall thymic cellularity in the null mice was severely reduced, affecting all developmental stages of the alpha-beta T-cell lineage.

Herzig et al. (2001) demonstrated that mice carrying a targeted disruption of the CREB protein gene, or overexpressing a dominant-negative CREB inhibitor, exhibit fasting hypoglycemia and reduced expression of gluconeogenic enzymes. CREB induces expression of the gluconeogenic program through the nuclear receptor coactivator PGC1 (604517), which was demonstrated to be a direct target for CREB regulation in vivo. Overexpression of PGC1 in CREB-deficient mice restored glucose homeostasis and rescued the expression of gluconeogenic genes. In transient assays, PGC1 potentiated glucocorticoid induction of the gene for PEPCK (614168), the rate-limiting enzyme in gluconeogenesis. PGC1 promotes cooperation between cAMP and glucocorticoid signaling pathways during hepatic gluconeogenesis. Fasting hyperglycemia is strongly correlated with type II diabetes (125853), so Herzig et al. (2001) concluded that the activation of PGC1 by CREB in liver contributes importantly to the pathogenesis of this disease.

Pittenger et al. (2002) interfered with the normal function of CREB family transcription factors in the dorsal hippocampus of transgenic mice expressing a mutant of human CREB, called KCREB (Walton et al., 1992), that is a dominant-negative inhibitor of the CREB family transcription factors CREB, CREM, and ATF1 (123803). Pittenger et al. (2002) observed that their KCREB transgenic animals were impaired in the Morris water maze test, which specifically requires the dorsal hippocampus. Results of an object recognition task showed that the deficit was specific to long-term memory. Several forms of LLTP were normal, but forskolin-induced and dopamine-regulated potentiation were disrupted. Pittenger et al. (2002) concluded that CREB has a role in hippocampus-dependent learning.

Kida et al. (2002) generated transgenic mice with an inducible and reversible CREB repressor by fusing CREB with a ser133-to-ala mutation to a tamoxifen-dependent mutant of an estrogen receptor ligand-binding domain. They found that CREB is crucial for the consolidation of long-term conditioned fear memories, but not for encoding, storage, or retrieval of these memories. Their studies also showed that CREB is required for the stability of reactivated or retrieved conditioned fear memories. Although the transcriptional processes necessary for the stability of initial and reactivated memories differ, CREB was found to be required for both.

Activation of CREB by phosphorylation has been implicated in the survival of mammalian cells. To define its roles in the mouse central nervous system, Mantamadiotis et al. (2002) disrupted Creb1 in brain of developing and adult mice using the Cre/loxP system. They found that mice with a genome background in which the cAMP response element modulator (CREM; 123812) had been knocked out and who also lacked Creb in the central nervous system during development showed extensive apoptosis of postmitotic neurons. By contrast, mice in which both Creb1 and Crem were disrupted in the postnatal forebrain showed progressive neurodegeneration in the hippocampus and in the dorsolateral striatum. The striatal phenotype was reminiscent of Huntington disease (143100) and consistent with the postulated role of CREB-mediated signaling in polyglutamine-triggered diseases.

By analyzing the Creb knockout mice generated by Rudolph et al. (1998), Lonze et al. (2002) concluded that CREB is critical for several aspects of neuronal development. Creb-null mice exhibited excess apoptosis, degeneration of sensory neurons, and impaired axonal growth and projections. They concluded that CREB is required within sensory and sympathetic neurons for survival and axon extension because both of these neurotrophin-dependent processes were compromised in cultured neurons from the Creb-null mice. The authors hypothesized that CREB is a key nuclear target of neurotrophin-stimulated cellular events that are critical for the survival of peripheral neurons and for the proper establishment of the peripheral nervous system.

Herzig et al. (2003) generated mice infected with dominant-negative Creb-expressing adenovirus and showed that, compared with control littermates, the Creb-deficient mice had a fatty liver phenotype and a pronounced increase in hepatic triglyceride content and in plasma triglyceride levels on a high-fat diet. The heterozygotes also displayed higher liver triglyceride contents than wildtype littermates. Creb-deficient mice displayed elevated expression of the nuclear hormone receptor Ppar-gamma (601487). CREB inhibits hepatic PPAR-gamma expression in the fasted state by stimulating the expression of the hairy/enhancer of split (HES1; 139605) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo. Herzig et al. (2003) concluded that the coordinate induction of PGC1 and repression of PPAR-gamma by CREB during fasting provides a molecular rationale for the antagonism between insulin and counter-regulatory hormones, and indicates a potential role for CREB antagonists as therapeutic agents in enhancing insulin sensitivity in the liver.

Berdeaux et al. (2007) found that transgenic mice expressing a dominant-negative form of Creb (A-Creb) in muscle exhibited a dystrophic phenotype accompanied by extensive fiber necrosis and reduced Mef2 (see 600660) activity. Class II HDAC (see HDAC5; 605315) phosphorylation was decreased in A-Creb myofibers due to a reduction in the levels of Sik1 (SNF1LK; 605705), a Creb target gene that functions as a class II HDAC kinase. Inhibition of class II HDAC activity via expression of Sik1 or a small molecule inhibitor ameliorated the dystrophic phenotype of mice expressing A-Creb in muscle, suggesting that the SIK1-HDAC pathway has a role in regulating muscle function.


ALLELIC VARIANTS 1 Selected Example):

.0001   VARIANT OF UNKNOWN SIGNIFICANCE

CREB1, ASP116GLY
SNP: rs387906617, ClinVar: RCV000022519

This variant is classified as a variant of unknown significance because its contribution to a lethal multiple malformation syndrome has not been confirmed.

By targeted sequencing of the CREB1 gene in a newborn with multiple congenital anomalies, Kitazawa et al. (2012) identified a de novo heterozygous 347A-G transition in the CREB1 gene, resulting in an asp116-to-gly (D116G) substitution in the kinase-inducible domain (KID) of the protein. The CREB1 gene was chosen for sequencing because the phenotype closely resembled that of Creb-null mice (Rudolph et al., 1998). The patient was born with agenesis of the corpus callosum, cerebellar hypoplasia, severe neonatal respiratory distress refractory to surfactant, thymus hypoplasia, and thyroid follicular hypoplasia, and died at age 26 weeks. In vitro functional expression studies in HEK293 cells showed that the mutant D116G protein had an inhibitory effect on transcriptional activity. Although the mutant protein was phosphorylated at ser133 after forskolin treatment, it failed to associate with transcriptional coactivators CREBBP (600140) and EP300 (602700), suggesting that the mutant protein had an altered 3-dimensional structure. The mutant protein blocked the transactivation of target genes in a dominant-negative manner. Kitazawa et al. (2012) noted that the protein kinase A/CREBBP/EP300 pathway is also impaired in Rubinstein-Taybi syndrome (see RSTS1, 180849).


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Contributors:
Patricia A. Hartz - updated : 10/19/2017
Ada Hamosh - updated : 01/15/2015
Cassandra L. Kniffin - updated : 4/16/2012
Ada Hamosh - updated : 6/29/2011
Ada Hamosh - updated : 8/24/2010
Ada Hamosh - updated : 4/7/2009
Cassandra L. Kniffin - updated : 7/3/2008
Paul J. Converse - updated : 10/11/2007
Ada Hamosh - updated : 5/30/2007
John Logan Black, III - updated : 8/22/2006
John Logan Black, III - updated : 6/9/2005
Ada Hamosh - updated : 2/25/2005
Patricia A. Hartz - updated : 6/25/2004
John A. Phillips, III - updated : 2/10/2004
Ada Hamosh - updated : 12/3/2003
John Logan Black, III - updated : 7/17/2003
Dawn Watkins-Chow - updated : 5/20/2003
Dawn Watkins-Chow - updated : 12/17/2002
John A. Phillips, III - updated : 7/23/2002
Victor A. McKusick - updated : 5/6/2002
Ada Hamosh - updated : 3/28/2002
Stylianos E. Antonarakis - updated : 3/25/2002
Ada Hamosh - updated : 9/12/2001
Paul J. Converse - updated : 4/27/2001
Victor A. McKusick - updated : 12/17/1998
Victor A. McKusick - updated : 6/26/1998
Stylianos E. Antonarakis - updated : 1/23/1998

Creation Date:
Victor A. McKusick : 7/5/1990

Edit History:
alopez : 06/13/2022
carol : 10/20/2017
mgross : 10/19/2017
alopez : 01/15/2015
carol : 7/8/2014
carol : 11/2/2012
carol : 6/5/2012
alopez : 4/20/2012
ckniffin : 4/16/2012
carol : 11/22/2011
alopez : 7/5/2011
alopez : 7/5/2011
terry : 6/29/2011
terry : 5/17/2011
mgross : 8/25/2010
terry : 8/24/2010
alopez : 4/8/2009
terry : 4/7/2009
wwang : 7/8/2008
ckniffin : 7/3/2008
mgross : 10/11/2007
alopez : 6/14/2007
terry : 5/30/2007
carol : 8/22/2006
carol : 6/9/2005
terry : 3/14/2005
carol : 3/9/2005
wwang : 3/9/2005
wwang : 3/2/2005
terry : 2/25/2005
mgross : 6/30/2004
terry : 6/25/2004
alopez : 2/10/2004
tkritzer : 2/3/2004
alopez : 12/4/2003
alopez : 12/4/2003
terry : 12/3/2003
terry : 8/15/2003
carol : 7/21/2003
terry : 7/17/2003
carol : 5/20/2003
carol : 2/4/2003
tkritzer : 12/17/2002
tkritzer : 12/17/2002
tkritzer : 7/23/2002
alopez : 5/6/2002
alopez : 5/6/2002
alopez : 4/12/2002
mgross : 3/29/2002
terry : 3/28/2002
mgross : 3/25/2002
terry : 11/15/2001
carol : 11/7/2001
alopez : 9/12/2001
terry : 9/12/2001
mgross : 4/27/2001
mgross : 4/27/2001
alopez : 8/28/2000
alopez : 12/17/1998
dkim : 10/20/1998
carol : 6/30/1998
dkim : 6/30/1998
terry : 6/26/1998
terry : 6/26/1998
carol : 1/26/1998
carol : 1/23/1998
mark : 2/15/1996
mark : 2/8/1996
carol : 11/5/1992
carol : 8/13/1992
supermim : 3/16/1992
carol : 2/28/1992
carol : 7/5/1990



NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2024 Johns Hopkins University.

NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2024 Johns Hopkins University.
Printed: April 29, 2024