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CREB

The cAMP response element-binding protein (CREB) is a nuclear transcription factor that binds to specific DNA sequences known as cAMP response elements (CRE), typically the palindromic motif 5'-TGACGTCA-3', to regulate the expression of target genes in response to cyclic AMP (cAMP) and other signaling molecules. Activated primarily by phosphorylation at serine 133, CREB recruits coactivators such as CREB-binding protein (CBP) and p300 to stimulate transcription, playing essential roles in cellular processes including neuronal survival, synaptic plasticity, and long-term memory formation.^[1] Discovered through its interaction with the somatostatin gene promoter, CREB controls over 4,000 genes and is conserved across eukaryotes, underscoring its fundamental importance in signal transduction.^[2] Encoded by the CREB1 gene on human chromosome 2q33.3, CREB is a 43 kDa protein consisting of 341 amino acids, structured into distinct functional domains that enable its regulatory functions.^[3] The N-terminal region includes the glutamine-rich Q1 and Q2 activation domains for basal and constitutive transactivation, while the central kinase-inducible domain (KID) harbors the key serine 133 phosphorylation site; the C-terminal basic leucine zipper (bZIP) domain facilitates homo- or heterodimerization with related factors like CREM or ATF-1 and specific DNA binding to CRE sites.^[1] The gene spans 11 exons, and alternative splicing produces isoforms such as CREBα (full-length, most active), CREBβ (lacking part of Q2), and CREBΔ (truncated, often inhibitory), which exhibit tissue-specific expression and varying transcriptional potencies.^[2] CREB activation occurs via phosphorylation at serine 133 by multiple kinases, including protein kinase A (PKA) in response to cAMP elevation through G-protein-coupled receptors, calcium/calmodulin-dependent kinases (CaMKs) triggered by neuronal activity, and mitogen-activated protein kinases (MAPKs) or Akt downstream of growth factors like brain-derived neurotrophic factor (BDNF).^[1] This modification enhances CREB's affinity for coactivators, leading to histone acetylation and chromatin remodeling at target promoters to drive gene expression for proteins involved in survival (e.g., Bcl-2), plasticity (e.g., BDNF), and metabolism. Inactivation involves dephosphorylation by protein phosphatases such as PP1, PP2A, and calcineurin (PP2B), ensuring signal specificity.^[2] In the central nervous system, CREB is highly expressed in regions like the hippocampus, cortex, and nucleus accumbens, where it mediates dopamine D1 receptor signaling to promote reward, mood regulation, and addiction-related behaviors, while its role in long-term potentiation (LTP) and neurogenesis is vital for learning and memory.^[1] Dysregulation of CREB contributes to pathologies including schizophrenia (with reduced expression in the cingulate gyrus and genetic variants like -933T>C), depression, and Alzheimer's disease (via impaired BDNF signaling).^[1] CREB is also implicated in various cancers (e.g., overexpression in acute myeloid leukemia driving proliferation).^[2] Therapeutic strategies targeting CREB, such as small-molecule inhibitors (e.g., 666-15) or enhancers, are under investigation for neurodegenerative and oncological conditions.^[2]

Structure and Subtypes

Protein Domains and Motifs

The CREB protein, a member of the bZIP transcription factor family, features a modular architecture with distinct domains that underpin its molecular interactions. At its C-terminus lies the basic leucine zipper (bZIP) domain, comprising a basic region for DNA contact and a leucine zipper motif for dimerization, which enables CREB to form homodimers or heterodimers with related proteins such as ATF-1 or CREM.^[4] This domain's structure has been elucidated through crystallographic studies, revealing how the leucine zipper coils into an α-helical dimer that positions the basic regions to insert into the major groove of DNA.^[5] Central to CREB's regulatory potential is the kinase-inducible domain (KID), located in the N-terminal region between two glutamine-rich segments, which harbors the critical Ser133 phosphorylation site within a flexible, intrinsically disordered sequence.^[4] The KID's structural plasticity allows it to adopt transient helical conformations upon interaction with binding partners, as observed in NMR studies of its phosphorylated form. Adjacent to the KID, the transactivation domain (TAD) consists of glutamine-rich regions (Q1 and Q2) that are largely unstructured in isolation but facilitate recruitment of co-activators through hydrophobic and electrostatic interactions, with Q1 associating with TAFII135 and Q2 with C/EBP-like factors.^[4] Recent analyses highlight the TAD's glutamine-rich motifs as enabling dynamic, low-affinity binding surfaces for multi-partner assemblies.^[6] CREB exhibits sequence-specific DNA binding via its bZIP domain, preferentially recognizing the palindromic cAMP response element (CRE) consensus sequence TGACGTCA, where the central CGTCA core is contacted by conserved basic residues, often enhanced by divalent cations like magnesium. This specificity is conserved in variant CRE half-sites such as CGTCA or TGACG, allowing flexible promoter interactions.^[4] Nuclear localization is directed by a bipartite nuclear localization signal (NLS), a short basic peptide sequence (RRKKK) embedded between the basic region and leucine zipper of the bZIP domain, which interacts with importin proteins to mediate active transport across the nuclear pore complex and maintain predominantly nuclear distribution.^[4] The structural domains of CREB demonstrate remarkable evolutionary conservation, with the Q1, KID, Q2, and bZIP motifs present from basal metazoans like hydra to vertebrates, reflecting their fundamental role in transcriptional control across species.^[4] Sequence identity in the bZIP domain exceeds 80% between mammals and Drosophila, underscoring selective pressure on DNA-binding and dimerization elements.^[7]

Isoforms and Family Variants

The CREB family encompasses several transcription factors characterized by a conserved basic leucine zipper (bZIP) domain that facilitates DNA binding and dimerization, with isoforms exhibiting distinct structural features that influence their regulatory roles.^[4] CREB1 serves as the prototypical member of the family, encoded by the CREB1 gene and primarily expressed as the α isoform, which includes a full N-terminal transactivation domain rich in glutamine and contributing to robust transcriptional activation upon phosphorylation. In contrast, the β isoform arises from alternative splicing that truncates this glutamine-rich region, resulting in reduced transactivation potential while retaining the bZIP domain for DNA interaction. These structural differences allow the α isoform to more effectively recruit coactivators like CBP/p300, whereas the β variant may function in a partially repressive or modulatory capacity.^[8]^[9] CREB2, also known as ATF4, represents a distinct family variant that functions predominantly as a transcriptional repressor, featuring a bZIP domain with specificity for CRE-like elements but lacking strong activation motifs in its N-terminal region. This isoform's repressive activity stems from its ability to form heterodimers with other bZIP proteins, such as ATF3, thereby competing with activator isoforms like CREB1 for binding sites and inhibiting gene expression, particularly under stress conditions.^[10]^[4] The CREB3 subfamily, comprising CREB3 and its paralogs CREB3L1 through CREB3L4, differs markedly from soluble CREB variants by incorporating a transmembrane domain that anchors them to the endoplasmic reticulum (ER) membrane. These isoforms are activated through regulated intramembrane proteolysis during ER stress, releasing a soluble N-terminal fragment containing the bZIP domain for nuclear translocation and target gene regulation, with each member (e.g., CREB3L1/OASIS) showing variations in the basic region that confer specificity to stress-responsive elements.^[11] CREB5, alternatively termed CRE-BP1, is another family variant notable for its involvement in developmental processes, where it acts as a CRE-dependent trans-activator capable of homodimerization or heterodimerization with c-Jun to regulate genes essential for tissue patterning, such as those in synovial joint formation. Structurally, it shares the bZIP motif but possesses an extended activation domain that supports its role in early embryonic regulation without the transmembrane features of the CREB3 group.^[4] Alternative splicing patterns within the CREB1 gene, particularly at exon 9, generate the α and β isoforms, while additional rare variants like Δ (lacking 14 amino acids near the N-terminus) arise from exon skipping, altering nuclear localization and coactivator binding efficiency. Post-translational modifications unique to specific isoforms include isoform-selective SUMOylation on lysine residues in the transactivation domain of CREB1Δ, which enhances its stability and repressive potential under certain conditions, contrasting with the more ubiquitous Ser133 phosphorylation across family members that activates the kinase-inducible domain.^[8]^[4]^[12] The genomic organization of CREB genes reflects their evolutionary divergence; for instance, CREB1 spans approximately 76 kb on human chromosome 2q33.3, with a total of 17 exons across transcripts where the main isoform spans 8 exons that encode the functional domains, with regulatory elements in intronic regions facilitating isoform diversity. Similar multi-exon structures are observed in other family members, such as ATF4 (CREB2) on chromosome 22q13.1 and CREB3 on chromosome 9p13.3, underscoring the role of splicing in generating variant-specific transcripts.^[3]

Activation and Mechanism

Phosphorylation and Signaling Pathways

CREB activation primarily occurs through phosphorylation at serine 133 (Ser133), a critical modification that enables its interaction with co-activators and subsequent transcriptional function. This site, located within the kinase-inducible domain (KID), is targeted by multiple kinases in response to diverse extracellular signals.^[13] The cAMP-dependent pathway represents one of the earliest identified mechanisms for CREB phosphorylation. Elevation of intracellular cAMP levels activates protein kinase A (PKA), which directly phosphorylates CREB at Ser133. This process was first demonstrated in studies showing that forskolin-induced cAMP elevation leads to a six-fold increase in CREB phosphorylation in PC12 cells, correlating with enhanced somatostatin gene transcription.^[13] PKA-mediated phosphorylation is transient, as the signal attenuates over time to prevent prolonged activation.^[1] Calcium influx, often triggered by NMDA receptor activation in neurons, engages the calcium/calmodulin-dependent kinase (CaMK) pathway to phosphorylate CREB at Ser133. CaMKIV, activated by calmodulin in response to elevated intracellular calcium, directly targets this residue, as shown in depolarization experiments where CREB phosphorylation increases following calcium entry through voltage-sensitive channels or NMDA receptors.^[14] This pathway contributes to activity-dependent gene expression, with CaMKII also participating by phosphorylating CREB, though less potently at Ser133 compared to CaMKIV. Growth factors initiate CREB phosphorylation via the mitogen-activated protein kinase (MAPK/ERK) cascade, which indirectly modifies Ser133 through downstream effectors. ERK activation leads to the phosphorylation and activation of ribosomal S6 kinase (RSK), which then targets CREB at Ser133; this was established in PC12 cells where nerve growth factor stimulates CREB phosphorylation via the Ras-MAPK-RSK pathway.^[15] Similarly, mitogen- and stress-activated kinase (MSK1/2), activated by both ERK and p38 MAPK, phosphorylates CREB at the same site, providing an additional layer of regulation in response to mitogenic or stress signals. Dephosphorylation of CREB at Ser133 is mediated primarily by protein phosphatase 1 (PP1), which counteracts kinase activity to terminate signaling. In PC12 cells, PP1 inhibition prolongs CREB phosphorylation and sustains cAMP-responsive transcription, indicating its role in signal attenuation.^[16] PP1 activity is regulated by inhibitory proteins and neuronal activity; for instance, NMDA receptor stimulation can modulate PP1 anchoring via proteins like inhibitor-1, fine-tuning the duration of CREB activation.^[17] Protein phosphatase 2A (PP2A) also contributes to dephosphorylation, particularly in contexts involving sustained signals.^[18] These pathways exhibit significant crosstalk, allowing CREB to integrate multiple signals for nuanced responses. For example, calcium influx can enhance cAMP/PKA signaling by activating ERK through Rap1-B-Raf, thereby amplifying Ser133 phosphorylation in a cooperative manner.^[19] Similarly, MAPK activation can synergize with CaMK pathways during neuronal stimulation, where initial calcium signals prime ERK-dependent CREB modification for prolonged effects, as observed in hippocampal neurons.^[20] This integration ensures CREB responds adaptively to combined cAMP, calcium, and growth factor inputs without isolated pathway dominance.

Transcriptional Regulation Process

Phosphorylated at serine 133 in the nucleus, CREB binds as a homodimer or heterodimer to the cAMP response element (CRE) consensus sequence TGACGTCA in the promoter regions of target genes.^[21]^[22] This phosphorylation-induced conformational change in CREB's kinase-inducible domain (KID) enables specific recruitment of the co-activators CREB-binding protein (CBP) and p300 through interaction with their KIX domains, forming a multiprotein complex at the CRE site.^[23] CBP and p300 possess intrinsic histone acetyltransferase (HAT) activity, which acetylates histones H3 and H4 at the promoter, leading to chromatin decondensation and enhanced accessibility for the basal transcriptional machinery, thereby facilitating RNA polymerase II recruitment and transcriptional initiation. Activated CREB-CBP/p300 complexes drive the transcription of diverse target genes, including the immediate early genes c-fos, Arc, and BDNF, which encode proteins involved in cellular responses to stimuli.^[24]^[25] Target gene selection is influenced by the combinatorial presence of CRE sites alongside other regulatory elements and the local chromatin landscape, allowing context-specific transcriptional outputs. In addition to activation, CREB exhibits repressive functions through interactions with specific isoforms, such as the inducible cAMP early repressor (ICER), a truncated CREM isoform lacking transactivation domains that competes for CRE binding and blocks activator recruitment.^[26] Certain CREB family members can also associate with co-repressors to inhibit transcription, contributing to fine-tuned regulation of gene expression.^[27] CREB-mediated transcription often involves feedback loops that amplify output; for instance, activation of BDNF by CREB promotes further CREB phosphorylation and activity, establishing a positive autoregulatory circuit that sustains transcriptional responses.^[24] Negative feedback can arise from induced repressors like ICER, which dampen prolonged activation to prevent overexpression.^[26]

Physiological Roles

Functions in the Nervous System

CREB plays a central role in neuronal plasticity and survival within the central nervous system, particularly by regulating gene expression in response to synaptic activity. As a transcription factor, it is activated through phosphorylation in key brain regions, enabling the expression of genes essential for adaptive neural processes.00828-0) In the hippocampus and cerebral cortex, CREB exhibits distinct expression patterns that support its involvement in learning and memory. CREB protein levels and phosphorylation are elevated in hippocampal neurons following neuronal activity, such as during seizures or synaptic stimulation, with peak phosphorylation occurring 3-8 minutes post-stimulation.^[28] In the cortex, CREB expression is modulated by chronic stimuli like antidepressants, leading to increased levels that correlate with enhanced neuronal responsiveness.^[29] These regional patterns underscore CREB's localized contributions to synaptic strengthening in areas critical for cognitive function.^[30] CREB regulates long-term potentiation (LTP), a cellular mechanism underlying memory formation, by promoting the transcription of target genes such as BDNF and c-fos. Activation of CREB facilitates the late phase of LTP (L-LTP) in hippocampal CA1 neurons, where expression of a constitutively active VP16-CREB variant lowers the threshold for L-LTP induction and enhances synaptic capture of plasticity-related proteins.00657-8) BDNF, a key CREB target, is essential for maintaining LTP and consolidating long-term memory traces, as demonstrated by studies showing that BDNF infusion transforms short-term memory into persistent forms via ERK-dependent CREB signaling.^[31] Similarly, CREB-driven c-fos expression supports structural changes at synapses during memory consolidation.^[32] CREB contributes to synaptic plasticity through the ERK-CREB signaling pathway, which transmits signals from synapses to the nucleus. ERK activation at synapses leads to CREB phosphorylation in the nucleus, enabling transcriptional responses that sustain plasticity; recent findings indicate this process requires dendrite-to-soma calcium propagation mediated by L-type voltage-gated calcium channels.^[33] In 2025 research, disruption of this synapse-to-nucleus transport in hippocampal neurons impaired CREB-dependent immediate early gene expression, such as c-fos, highlighting its necessity for activity-induced plasticity.^[34] CREB provides neuroprotection against excitotoxic insults and ischemic damage by activating anti-apoptotic genes in vulnerable neurons. Synaptic activity-dependent CREB phosphorylation protects cortical neurons from NMDA-induced excitotoxicity, with dominant-negative CREB constructs exacerbating cell death.^[35] In models of cerebral ischemia, non-canonical CREB activation—independent of traditional phosphorylation—confers resistance to glutamate-mediated necrosis, as observed in neuronal cultures exposed to excitotoxic levels of glutamate.^[36] These protective effects are most pronounced in moderately stressed neurons, emphasizing CREB's role in buffering against acute brain injuries.^[37] In reward and addiction pathways, CREB modulates dopamine signaling to influence motivational behaviors. Within the nucleus accumbens, drugs of abuse like cocaine activate CREB via dopamine D1 receptors, promoting dynorphin expression that attenuates reward sensitivity and contributes to tolerance development.^[38] Overexpression of dominant-negative CREB in D1-expressing neurons enhances cocaine-induced locomotor activity and conditioned place preference, indicating CREB's suppressive role in reward escalation. This dopamine-CREB axis helps regulate the transition from acute reinforcement to chronic dependence.^[39] Animal models, particularly CREB knockout mice, reveal deficits in memory formation that affirm its physiological necessity. CREBαΔ mutant mice exhibit impaired long-term memory in tasks like fear conditioning and spatial navigation, despite normal short-term memory, due to disrupted gene dosage in hippocampal circuits.^[40] These mutants show reduced LTP maintenance and fail to consolidate memories under spaced training paradigms, underscoring CREB's requirement for protein synthesis-dependent plasticity.^[41] Such studies in mice have established CREB as a core mediator of hippocampus-dependent learning.^[42]

Roles in Circadian Rhythms and Peripheral Tissues

CREB plays a pivotal role in the entrainment of mammalian circadian rhythms through its phosphorylation in the suprachiasmatic nucleus (SCN), the primary circadian pacemaker in the hypothalamus. Light exposure during the subjective night induces phosphorylation of CREB at serine 133, which activates transcription of clock genes such as Per1 and Per2, facilitating phase shifts in behavioral rhythms.^[43] This phosphorylation exhibits a circadian rhythmicity, occurring preferentially during the light-inducible phase when it synchronizes downstream clock components.^[44] The link between CREB and circadian regulation was first established in the 1990s through studies demonstrating that light pulses trigger rapid CREB activation in the SCN, leading to immediate-early gene expression and clock resetting.^[43] Furthermore, CREB-dependent activation of Per1 is essential for glutamatergic signaling-mediated phase resetting in the SCN.^[45] In peripheral tissues, CREB regulates hepatic gluconeogenesis primarily via the CREB-CRTC2 axis, which integrates fasting signals to maintain blood glucose levels. During fasting, dephosphorylation of CRTC2 allows its nuclear translocation and coactivation of CREB, driving expression of gluconeogenic enzymes like Pck1 and G6pc. This pathway links endoplasmic reticulum stress to enhanced gluconeogenesis, ensuring metabolic adaptation to nutrient deprivation.^[46] Hepatic CRTC2 also modulates whole-body energy homeostasis by influencing microRNA-mediated suppression of gluconeogenic genes under fed conditions.^[47] CREB contributes to immune function by promoting T-cell differentiation and cytokine production, particularly interleukin-2 (IL-2), which is crucial for T-cell proliferation and effector responses. Upon T-cell receptor stimulation, phosphorylated CREB binds to the Il2 promoter, enhancing its transcription and supporting adaptive immunity.^[48] In Th17 cells, the CREB/CRTC2 pathway, activated by prostaglandin E2, drives differentiation and autoimmune responses by upregulating RORγt-dependent genes.^[49] Overall, CREB orchestrates diverse immune cellular responses, including survival and subset specification in lymphocytes.^[50] Recent research highlights CREB's involvement in renal water balance, where vasopressin stimulates CREB-family transcription factors to regulate Aqp2 expression in the collecting duct, promoting aquaporin-2-mediated water reabsorption.^[51] Disruption of this CREB-mediated Aqp2 transcription impairs vasopressin responsiveness, leading to altered urine concentration.^[52] In the cardiovascular system, the CREB3 family member regulates endothelial cell functions, including vascular homeostasis and response to stress, by modulating genes involved in angiogenesis and inflammation.^[53] CREB3 influences endothelial integrity through pathways affecting adhesion molecules like PECAM-1, contributing to cardiovascular disease prevention.^[54]

Disease Associations

Neurological and Neurodegenerative Disorders

In Alzheimer's disease (AD), reduced phosphorylation of CREB in the hippocampus and prefrontal cortex has been observed in postmortem brain tissues, leading to impaired transcription of memory-related genes such as BDNF and contributing to synaptic dysfunction and cognitive decline.^[55] Beta-amyloid peptides disrupt CREB-mediated gene transcription essential for long-term potentiation and neuronal survival, exacerbating memory deficits in AD models and human patients.^[56] Overexpression of BACE1, a key enzyme in amyloid-beta production, further decreases CREB phosphorylation and cAMP/PKA signaling, linking amyloid pathology directly to CREB dysregulation.^[57] These findings from postmortem analyses highlight CREB's role in AD progression, with chronic downregulation of CREB content in hippocampal neurons correlating with advanced disease stages.^[58] In amyotrophic lateral sclerosis (ALS), gain-of-function variants in CREB3, particularly the R119G mutation, confer protection by reducing disease risk and slowing motor progression through enhanced CREB3 activity in motor neurons and glia.^[59] This variant activates resilience pathways against endoplasmic reticulum stress and altered mRNA translation in cortical spinal neurons, as evidenced by cross-species transcriptomic studies and patient cohort analyses. In Parkinson's disease (PD), alpha-synuclein aggregates impair CREB's transcriptional regulation of survival genes in dopaminergic neurons by interfering with CRE-dependent processes without directly inhibiting CREB phosphorylation, promoting neurodegeneration in the substantia nigra.^[60] Postmortem PD brain tissues show diminished CREB signaling, consistent with alpha-synuclein's nuclear entry and disruption of CREB-dependent processes without direct binding.^[61] Genome-wide association studies (GWAS) implicate the broader cAMP/PKA/CREB pathway in neurodegenerative risks, though direct hits on CREB genes remain limited, supporting pathway-level associations from AD and PD genetic data.^[62] Depression and mood disorders are associated with impaired CREB activity in the hippocampus, where reduced CREB-BDNF signaling contributes to neuroplasticity deficits and depressive behaviors in both rodent models and human patients.^[63] Chronic stress elevates hippocampal salt-inducible kinase 2, which inhibits CREB-regulated transcription coactivator 1 (CRTC1), leading to decreased CREB phosphorylation and exacerbated mood dysregulation.^[64] Overexpression of CREB in the hippocampal CA1 region induces depression-like behaviors, underscoring its context-dependent role in mood regulation. In the context of neurodegeneration, CREB activation in reactive astrocytes modulates astrogliosis, with targeted CREB signaling in these cells providing neuroprotection against secondary injury in models of traumatic brain injury and potentially in chronic conditions like AD.^[65]

Cancer and Other Pathologies

CREB overexpression has been implicated in promoting breast cancer progression, where elevated levels correlate with increased tumor aggressiveness and poor patient prognosis. Specifically, CREB enhances breast cancer cell proliferation, survival, invasion, and metastasis by acting as a transcription factor that aberrantly regulates genes involved in cell cycle progression and apoptosis resistance. In addition, CREB contributes to therapy resistance in breast cancer through the deregulation of anti-apoptotic genes such as Bcl-2, thereby allowing cancer cells to evade chemotherapy and targeted treatments.^[66] Recent studies utilizing tumor sequencing and knockout models have further elucidated CREB's oncogenic role across various cancers. Transcriptomic analyses of primary and metastatic breast tumors have revealed enrichment of cAMP/PKA/CREB signaling pathways, particularly in invasive lobular carcinoma, supporting its association with metastatic potential.^[67] In preclinical knockout models, CREB1 deletion in prostate cancer cells reduced tumor growth and restored expression of proliferation-related genes, highlighting its necessity for castration-resistant progression.^[68] Similarly, CREB inhibition in pancreatic ductal adenocarcinoma models derived from alcoholic pancreatitis decreased acinar-to-ductal reprogramming and primary tumor burden, underscoring its pro-tumorigenic effects in genetically modified mice.^[69] Beyond oncology, CREB dysregulation contributes to metabolic disorders such as type 2 diabetes by altering hepatic gluconeogenesis. In diabetic states, hyperactivation of CREB, often in concert with FoxO1, upregulates gluconeogenic enzymes like PEPCK and G6Pase, leading to excessive glucose production and hyperglycemia.^[70] This mechanism is exacerbated during fasting or insulin resistance, where impaired CREB regulation fails to suppress gluconeogenesis appropriately. In cardiovascular pathologies, the CREB3 subfamily member plays a key role in fibrosis and hypertrophy. CREB3 promotes vascular fibrosis in atherosclerosis by upregulating chemokine receptors CCR1 and CCR2, which enhance monocyte recruitment and smooth muscle cell migration via NF-κB-mediated MMP-9 expression.^[71] Conversely, CREB3 overexpression in endothelial cells mitigates cardiac hypertrophy through the HO-1/AKT pathway, reducing myocardial swelling and dysfunction in hypertensive models.^[71] CREB also influences immune dysregulation in autoimmune diseases, notably systemic lupus erythematosus (SLE). Reduced CREB activity and phosphorylation in SLE T cells, stemming from decreased protein kinase A signaling, impair regulatory T cell function and promote autoreactive responses.^[72] This imbalance, coupled with elevated CREM expression, contributes to T cell hyperactivity and autoantibody production characteristic of lupus pathology.^[72]

Therapeutic Implications

Modulators and Inhibitors

Small molecule inhibitors targeting the interaction between CREB and its coactivator CREB-binding protein (CBP) have been developed to disrupt CREB-mediated transcriptional activity. For instance, 666-15 is a potent naphthamide derivative that specifically inhibits the recruitment of CBP to phosphorylated CREB at Ser133, thereby blocking CREB-dependent gene transcription without directly binding CREB or CBP. This compound exhibits high selectivity and has demonstrated efficacy in suppressing CREB-driven processes in cellular models.^[73] Proteolysis-targeting chimeras (PROTACs) represent an advanced strategy for modulating CREBBP (the gene encoding CBP) by inducing its ubiquitin-mediated degradation, leveraging structural insights into the protein's domains. A 2025 review highlights how structure-based design of PROTACs, such as those incorporating ligands for the bromodomain or HAT domain of CREBBP, enables selective degradation while sparing related proteins like EP300. These degraders exploit crystallographic data to optimize linker lengths and E3 ligase recruiters, achieving potent and sustained reduction in CREBBP levels in preclinical settings. For example, dCE-2, a CBP/EP300 degrader, has shown promising specificity based on these structural principles.^[74]^[75] Activators of CREB often enhance its pathway indirectly by increasing cAMP levels, which promote phosphorylation at key sites like Ser133. Rolipram, a selective phosphodiesterase 4 (PDE4) inhibitor, elevates intracellular cAMP by preventing its hydrolysis, thereby amplifying PKA-mediated CREB activation and downstream transcription. This mechanism has been validated in various cell types, where rolipram dose-dependently increases CREB phosphorylation and target gene expression.^[76]^[77] Indirect modulation of CREB can be achieved through inhibitors of upstream kinase pathways, such as the mitogen-activated protein kinase (MAPK) cascade, which phosphorylates CREB via RSK kinases. MAPK/ERK pathway blockers like PD98059 or U0126 inhibit MEK, thereby reducing CREB phosphorylation and transcriptional output without directly targeting CREB. These agents selectively dampen MAPK-dependent CREB activation in response to growth factors or stress signals.^[20]^[15] For the CREB3 isoform, which is activated by proteolytic cleavage during endoplasmic reticulum (ER) stress, isoform-selective compounds are an emerging focus to modulate UPR responses without affecting canonical CREB. While specific small molecules remain limited, research emphasizes targeting CREB3's ER-Golgi trafficking and S1P/S2P-mediated processing, as seen with Golgi-dispersing agents that mobilize CREB3 under stress conditions. A 2024 review positions CREB3 as a therapeutic target for ER stress-related pathologies, highlighting the need for selective inhibitors to fine-tune its role in protein homeostasis.^[71] In preclinical models, CREB modulators have shown efficacy in addressing addiction and cancer. For cancer, 666-15 completely suppressed tumor growth in MDA-MB-468 xenografts by inhibiting CREB-CBP interactions, demonstrating tolerability and anti-proliferative effects. In addiction models, CREB inhibition via viral delivery of dominant-negative CREB in the nucleus accumbens reduced cocaine self-administration and attenuated reward-seeking behaviors, underscoring its role in countering drug-induced plasticity. Conversely, rolipram enhanced CREB activation to mitigate opiate withdrawal symptoms in rodent models of dependence.^[73]^[78]^[39]

Clinical and Research Developments

Recent advances in CREB-targeted interventions have highlighted its translational potential in neurodegenerative diseases, with Phase II clinical trials exploring CREB activators, such as PDE4 inhibitors like roflumilast, for cognitive enhancement in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Dual inhibitors of phosphodiesterase 4 (PDE4) and PDE10A have demonstrated restoration of CREB1 function and improved synaptic plasticity in preclinical AD models by elevating cAMP levels and promoting CREB phosphorylation at serine 133. These findings suggest potential for clinical translation aimed at memory restoration.^[79] In amyotrophic lateral sclerosis (ALS), post-2025 genetic studies have identified CREB3 as a promising therapeutic target following the discovery of gain-of-function variants that confer protection against disease onset and progression. The rare variant CREB3 R119G, which hyperactivates CREB3 transcription factor activity in response to endoplasmic reticulum stress, was found to reduce ALS risk by up to 50% and slow motor decline in carriers, as evidenced by large-scale genomic analyses of over 10,000 patients.^[59] This has spurred development of CREB3-targeted therapies, including small-molecule activators designed to mimic the variant's effects on unfolded protein response pathways, with preclinical models showing prolonged survival in ALS mouse strains through enhanced CREB3-mediated neuroprotection.^[80] Early-phase trials are anticipated to assess these activators' safety in modulating CREB3 hyperactivity without disrupting normal cellular homeostasis.^[81] A major challenge in advancing CREB-targeted therapies lies in achieving specificity, given CREB's ubiquitous expression across tissues and its essential role in diverse cellular processes such as proliferation, survival, and metabolism. Constitutive CREB activation is implicated in multiple pathologies, but broad inhibition risks systemic toxicity, as seen in early attempts to target CREB in cancers where off-target effects on non-malignant cells led to dose-limiting adverse events.^[82] Strategies to overcome this include tissue-specific delivery systems and isoform-selective modulators, which aim to restrict action to diseased neurons or tumor cells while sparing healthy ubiquitous CREB functions.^[27] Emerging proteolysis-targeting chimeras (PROTACs) offer a novel approach to degrade hyperactive CREB or its coactivators in cancer. PROTACs recruiting E3 ligases to ubiquitinate CREB-binding protein (CBP, a key CREB coactivator overexpressed in estrogen receptor-positive breast tumors) have shown selective degradation in preclinical models, reducing tumor growth without affecting normal mammary epithelium.^[83]^[84] Biomarker development has centered on phospho-CREB (p-CREB) levels as a dynamic indicator of CREB pathway activity, particularly in neurological contexts where reduced p-CREB correlates with synaptic loss in AD and ALS. High-intensity training interventions that boost p-CREB in the hippocampus have been associated with improved brain health, as reviewed in 2025 studies.^[85] In cancer, elevated p-CREB in tumor biopsies serves as a prognostic marker for immunotherapy response, guiding patient stratification in ongoing trials.^[86] Looking ahead, CREB modulation holds promise for circadian disorder treatments by targeting its interactions with clock genes like PER2, where disrupted CREB-PER2 crosstalk contributes to mood and sleep dysregulation. Pharmacological enhancement of CREB activity could synchronize peripheral clocks in shift workers or bipolar patients, with 2025 preclinical data suggesting improved rhythmicity via cAMP-PKA-CREB axis activation.^[87] In immunotherapies, inhibiting CREB in the tumor microenvironment reprograms stromal cells to enhance T-cell infiltration and checkpoint inhibitor efficacy in pancreatic cancer models.^[88] These developments underscore CREB's versatility, though long-term trials are needed to address specificity hurdles. Additional emerging strategies include natural compounds like curcumin analogs that activate CREB for neuroprotection in preclinical models of neurodegeneration, and gene therapy approaches such as AAV-delivered CREB enhancers, which show promise for restoring function in AD without systemic effects as of 2025.^[89]

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It can bind to the cAMP response element (CRE) sequence TGACGTCA or the conserved half CRE TGACG and was first identified in the somatostatin gene promoter [1].
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A Pivotal Role of Cyclic AMP-Responsive Element Binding Protein ...
CREB binds to CRE as a homodimer or heterodimer (7). It was demonstrated that Ser133 phosphorylation has no discernible effect on CREB DNA binding (8, 9, 10).
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Mechanism of CREB recognition and coactivation by the ... - PNAS
Although the bZip domain is widely known to play significant roles in DNA binding and dimerization, recent studies point to an additional role for this motif in ...
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CREB Family Transcription Factors Are Major Mediators of BDNF ...
Feb 12, 2020 · We show that CREB family transcription factors, together with the coactivator CBP/p300, but not the CRTC family, are the main regulators of rat BDNF gene ...Creb Family Of Transcription... · Creb Coactivator Crtc Does... · Creb Transcription Factor...
[21]
Article CREB: A Major Mediator of Neuronal Neurotrophin Responses
The fact that BDNF induces transcription through the Ca/CRE within c-fos is likely to have wide significance, since many neuronal genes contain CREs (Bonni et ...
[22]
Inducible cAMP Early Repressor (ICER) and Brain Functions - PMC
ICER is involved in the regulation of plasticity underlying epileptogenesis and fear memory, as well as reaction to stress.
[23]
Multi-faceted regulation of CREB family transcription factors - Frontiers
These conserved CREB proteins share common structural domains, and each of those domains is capable of regulating transcription (Figure 1). The DNA-binding and ...
[24]
Neuronal activity increases the phosphorylation of the transcription ...
We show that CREB phosphorylation is maximal between 3 and 8 min after the onset of seizure activity and declines slowly both in the hippocampus and the cortex.
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Expression of the cAMP response element binding protein (CREB ...
CREB expression and function in hippocampus are increased by chronic administration of different classes of antidepressants, including selective 5-HT and NE ...
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Altered Regulation of CREB by Chronic Antidepressant ... - Nature
Oct 30, 2001 · One explanation for the different expression patterns of CREB displayed by the cortex and hippocampus may be the upregulation of two cAMP ...
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BDNF is essential to promote persistence of long-term memory storage
We demonstrate that BDNF induces memory persistence by itself, transforming a nonlasting LTM trace into a persistent one in an ERK-dependent manner.Missing: via | Show results with:via
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A new perspective on the role of the CREB family of transcription ...
This review examines the CREB family of transcription factors, including the different members and known signaling pathways.
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Synapse-to-Nucleus ERK→CREB Transcriptional Signaling ...
Jan 22, 2025 · The cAMP-response element–binding protein (CREB) transcription factor controls the expression of the neuronal immediate early genes c-fos, ...
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Synapse-to-Nucleus ERK→CREB Transcriptional Signaling ...
Jan 22, 2025 · Synapse-to-Nucleus ERK→CREB Transcriptional Signaling Requires Dendrite-to-Soma Ca2+ Propagation Mediated by L-Type Voltage-Gated Ca2+ Channels.Missing: transport | Show results with:transport
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Activity-Dependent Neuroprotection and cAMP Response Element ...
Constitutively active and dominant-negative CREB constructs were used to implicate CREB in synaptic activity-dependent neuroprotection against NMDA-induced ...
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Non-Canonical Activation of CREB Mediates Neuroprotection in a C ...
Excitotoxicity is a major cause of neurodegeneration in brain ischemia, and the transcription factor cAMP Response Element Binding-protein (CREB) mediates ...
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Non‐canonical activation of CREB mediates neuroprotection in a ...
Nov 16, 2018 · We demonstrated that CREB's neuroprotective effect was conserved, and seemed most effective in neurons with moderate Glu exposure. We found that ...
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CREB activity in the nucleus accumbens shell controls ... - PNAS
Drugs of abuse activate CREB in the nucleus accumbens, an important part of the brain's reward pathways, and local manipulations of CREB activity have been ...
[35]
The Nuclear Transcription Factor CREB: Involvement in Addiction ...
Increasing evidence has supported a contribution of the nuclear transcription factor CREB in the development of addiction.
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Deficits in memory tasks of mice with CREB mutations ... - PubMed
Studies in Aplysia, Drosophila, and mice have shown that the transcription factor CREB is involved in formation and retention of long-term memory.
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Spaced training induces normal long-term memory in CREB mutant ...
CREBαΔ− mice show normal short-term but deficient long-term memory in a socially transmitted food preference task. To extend the studies of the CREBαΔ− mutants, ...Missing: knockout | Show results with:knockout
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Deficits in Memory Tasks of Mice with CREB Mutations Depend on ...
Studies in Aplysia, Drosophila, and mice have shown that the transcription factor CREB is involved in formation and retention of long-term memory.Missing: knockout | Show results with:knockout
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Regulation of CREB phosphorylation in the suprachiasmatic ...
Apr 9, 1993 · CREB became phosphorylated only at times during the circadian cycle when light induced IEG expression and caused phase shifts of circadian rhythms.
[40]
Regulation of CREB Phosphorylation in the Suprachiasmatic ...
CREB became phosphorylated only at times during the circadian cycle when light induced IEG expression and caused phase shifts of circadian rhythms.
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Ca2+/cAMP Response Element-binding Protein (CREB)-dependent ...
Ca2+/cAMP Response Element-binding Protein (CREB)-dependent Activation of Per1 Is Required for Light-induced Signaling in the Suprachiasmatic Nucleus Circadian ...
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Regulation of Hepatic Metabolism and Cell Growth by the ATF ...
Feb 15, 2021 · The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis . Nature. 2009. ;. 460. : 534. –. 537. Google Scholar · Crossref.
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Hepatic Crtc2 controls whole body energy metabolism via a miR ...
Nov 30, 2017 · Previously, Creb co-activator Crtc2 was shown to be essential in the regulation of chronic activation of gluconeogenesis in the liver, and it ...
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Transcriptional regulation of IL-2 in health and autoimmunity - PMC
The regulation of IL-2 production is central to our understanding of the immune system. Key during T cell activation, it also plays an essential role in the ...Foxp3 And The Regulation Of... · The Role Of Cd28... · Figure 2. Il2 Gene Promoter<|separator|>
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The CREB/CRTC2 pathway modulates autoimmune disease by ...
Jun 2, 2015 · Here we show that PGE 2 enhances Th17 cell differentiation via the activation of the CREB co-activator CRTC2.
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The Role of the Transcription Factor CREB in Immune Function - PMC
CREB is a transcription factor that regulates diverse cellular responses, including proliferation, survival, and differentiation.
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CREB-Family Transcription Factors and Vasopressin-Mediated...
Aug 26, 2025 · Water homeostasis is regulated by the peptide hormone arginine vasopressin, which promotes water reabsorption in the renal collecting duct.
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CREB-Family Transcription Factors and Vasopressin-Mediated ...
Aug 26, 2025 · The regulation of Aqp2 gene transcription is a key mechanism through which AVP modulates water transport as disruption of this mechanism leads ...Missing: kidney | Show results with:kidney
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CREB3 protein family: the promising therapeutic targets for ...
Nov 25, 2024 · (E, Zhang, Zhou, & Wang, 2014) During ER stress, CREB3 is transported to the Golgi apparatus, where it is sequentially cleaved by S1P and S2P.
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Decreased PECAM-1 May be a potential pathological factor ... - Nature
Jul 1, 2025 · Five regulatory factors, including CREB3 ... Among them, KDR is the receptor of VEGF (VEGFR-2), which mediates the regulation of endothelial cell ...The Pecam-1 Interaction... · Decreased Pecam-1 Is An... · Pecam-1 Transcription Gene...
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Reduced pCREB in Alzheimer's disease prefrontal cortex is ... - Nature
Aug 2, 2016 · Two papers have shown that total and activated CREB are reduced in the postmortem hippocampus of individuals with AD, which supports the idea ...
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beta-Amyloid disrupts activity-dependent gene transcription required ...
Jul 14, 2010 · In this study, we report that gene transcription mediated by the cAMP-response element binding protein (CREB)-regulated transcription ...
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Alzheimer's β-secretase (BACE1) regulates the cAMP/PKA/CREB ...
Aug 15, 2012 · We found that overexpression of BACE1 reduces cAMP response element binding protein (CREB) phosphorylation, protein kinase A (PKA) activity, and cAMP levels.
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Downregulation of CREB expression in Alzheimer's brain and in Aβ ...
Aug 19, 2011 · Our findings suggest that chronic downregulation of CREB-mediated transcription results in decrease of CREB content in the hippocampal neurons of AD brain.
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CREB3 gain of function variants protect against ALS - Nature
Mar 26, 2025 · Through gain of function, CREB3 R119G decreases the risk of developing ALS and the motor progression rate of ALS patients.
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Interference of alpha-synuclein with cAMP/PKA-dependent CREB ...
Alpha-SYN enters the nucleus, but does not bind to CREB or interfere with forskolin-induced CREB phosphorylation. These data indicate that elevated levels of α- ...
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Pathways to neurodegeneration: mechanistic insights from GWAS in ...
Here, we review and synthesize the major pathways implicated in neurodegeneration, focusing on GWAS from the most prevalent neurodegenerative disorders, AD and ...
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Hippocampal NR6A1 impairs CREB-BDNF signaling and leads to ...
May 15, 2022 · Chronic stress exposure is a risk factor that can induce the development of depression-like behaviors by impairing the hippocampal cyclic ...
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Hippocampal salt-inducible kinase 2 plays a role in depression via ...
Hippocampal salt-inducible kinase 2 plays a role in depression via the CREB-regulated transcription coactivator 1–cAMP response element ...
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Targeted activation of CREB in reactive astrocytes is neuroprotective ...
Here we report that the activation of CREB-dependent transcription in reactive astrocytes prevents secondary injury in cerebral cortex after experimental TBI.
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Dual PDE4/10A inhibition restores CREB1 function and enhances ...
Oct 27, 2025 · The human postmortem brain tissue samples: Mid-frontal cortices from brains of age-matched patients with AD (n = 6, 3 females and 3 males) ...<|separator|>
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The Journal of Pharmacology and Experimental Therapeutics
**Summary:**
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Transcriptomic analysis identifies enrichment of cAMP/PKA/CREB ...
Oct 30, 2024 · In an RNA expression dataset from paired primary and metastatic breast cancer, primary ILC had higher GSVA scores for cAMP/PKA/CREB ...Missing: JPET | Show results with:JPET
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CREB drives acinar cells to ductal reprogramming and promotes ...
Our findings demonstrate that CREB and Kras* promote irreversible ADM, accelerating pancreatic cancer progression with ACP. Targeting CREB may present a ...
[65]
CREB and FoxO1: two transcription factors for the regulation of ...
In this review, we would like to delineate the molecular mechanisms by which CREB and FoxO1 control the hepatic gluconeogenic program. We will also provide the ...
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CREB3 protein family: the promising therapeutic targets for ...
Nov 25, 2024 · Abstract. Significant advancements in cardiovascular and metabolic disease research have been made with the CREB3 protein family.Missing: fibrosis | Show results with:fibrosis
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The Pathology of T Cells in Systemic Lupus Erythematosus - PMC
There are at least 2 proposed mechanisms to explain the increased CREM and reduced CREB activities in lupus T cells. First, high levels of antilymphocytic ...
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Identification of a Potent Inhibitor of CREB-Mediated Gene ...
May 29, 2015 · This study demonstrates that the level of CREB1 in breast cancer patients is elevated and is significantly raised in patients with a poor ...
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CREB binding protein (CREBBP): Structure-based perspectives for ...
Aug 18, 2025 · Elaborates the structure and function of CBP systematically. Declares the small molecule inhibitors and PROTACs based on CBP structure.Missing: seminal | Show results with:seminal
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Structure-Based Design of CBP/EP300 Degraders - ACS Publications
Aug 8, 2024 · We present the development of dCE-2, a structurally novel PROTAC targeting the CREB-binding protein (CBP) and E1A-associated protein ...
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Action of rolipram on specific PDE4 cAMP phosphodiesterase ...
Rolipram increased phosphorylation of cAMP-response-element-binding protein (CREB) in U937 cells in a dose-dependent fashion.
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Identification of compounds that potentiate CREB signaling ... - PNAS
Feb 17, 2009 · PDEs rapidly degrade cAMP. Therefore, inhibition of PDE leads to a decrease in cAMP degradation, which in turn enhances CREB activation.
[73]
Inhibition of CREB activity in the dorsal portion of the striatum ...
Here we show, in startling contrast, that inhibition of striatal CREB facilitates cocaine- and morphine-place conditioning and enhances locomotor sensitization ...Missing: preclinical | Show results with:preclinical
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Dual PDE4/10A inhibition restores CREB1 function and enhances ...
Oct 27, 2025 · Inhibition of PDE4 has been shown to elevate cAMP levels, leading to enhanced CREB activation and improved cognitive function [24]. ... clinical ...
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CREB3 gain of function variants protect against ALS - PubMed
Mar 26, 2025 · Through gain of function, CREB3 R119G decreases the risk of developing ALS and the motor progression rate of ALS patients.Missing: Nature | Show results with:Nature
[76]
CREB3 protein identified as potential treatment target in ALS
Apr 9, 2025 · A rare mutation that leads to abnormally high activity of the CREB3 protein is associated with a reduced risk of developing amyotrophic lateral sclerosis (ALS).
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CREB in the Pathophysiology of Cancer: Implications for Targeting ...
CREB is overexpressed and constitutively phosphorylated in a number of forms of human cancer, including acute myeloid leukemia (AML) and non – small cell lung ...
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CREB binding protein (CREBBP): Structure-based perspectives for ...
BRD. The BRD is an evolutionarily highly conserved domain that exists in a variety of nuclear proteins. BRD consists of approximately 110 amino acids with a ...
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Proteolysis‐targeting chimeras in cancer therapy - NIH
Oct 18, 2025 · This review provides a comprehensive overview of developing PROTACs, from understanding their mechanism to clinical applications, and highlights ...
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High-intensity training on CREB activation for improving brain health
Jan 20, 2025 · CREB is crucial for neuronal development, and studies have shown that CREB deletion leads to neurodegeneration in the hippocampus and dentate ...
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CREB signaling activity correlates with differentiation and survival in ...
Aug 9, 2021 · We discovered that phosphorylation of transcription factor CREB strongly correlates with medulloblastoma survival and associates with a differentiation ...Missing: Biomarker | Show results with:Biomarker
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The crosstalk between CREB and PER2 mediates the transition ...
The crosstalk between CREB and PER2 mediates the transition between mania- and depression-like behavior. Neuropsychopharmacology. 2025 Oct;50(11):1683-1694.
[83]
Abstract 3290: Targeting CREB reprograms the tumor immune ...
Apr 21, 2025 · This study demonstrates the therapeutic advantage of targeting CREB to reprogram the stromal immune microenvironment and improve the efficacy of immunotherapy.