GO:0035497 cAMP response element binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0035497 cAMP response element binding is a molecular function defined as binding to the cyclic AMP response element (CRE), a short palindrome-containing promoter sequence that mediates cAMP-responsive transcription.
• The principal CRE-binding proteins are CREB family transcription factors, including CREB1, CREM and ATF1, which recognize the CRE palindrome and recruit coactivators such as CBP.
• CRE binding is regulated by phosphorylation of CREB at activating residues, and this phosphorylation-dependent switch is central to neuronal plasticity, circadian gene expression and metabolic gene control.
• CRE-mediated transcription controls physiologically important target genes such as Per1 in the circadian clock and TPH2 in serotonin biosynthesis.
• Dysregulated CRE binding contributes to human disease, including neurodegeneration, diabetic nephropathy and cancer-associated gene expression programs.
• CRISPR/Cas9 editing of CRE and flanking ETS sites provides a direct way to test whether a specific promoter element is required for target gene expression.
Description
GO:0035497 cAMP response element binding is the molecular function of selectively recognizing and binding the cyclic AMP response element (CRE), a short palindrome-containing DNA sequence found in the promoters of genes whose expression is regulated in response to cyclic AMP. This function is executed principally by CREB-family basic leucine zipper transcription factors, which convert cAMP-dependent signaling into changes in target gene transcription. Because CREs are embedded in the regulatory regions of many stimulus-responsive genes, CRE binding is a convergence point for hormonal, neuronal and metabolic signals.
cAMP response element binding At A Glance
| GO ID | GO:0035497 |
|---|---|
| GO term | cAMP response element binding |
| Ontology | molecular_function |
| Synonym | cAMP-responsive element binding; CRE binding; cyclic AMP response element binding; cyclic-AMP response element binding; cyclic-AMP-responsive element binding |
| Definition | Binding to a cyclic AMP response element (CRE), a short palindrome-containing sequence found in the promoters of genes whose expression is regulated in response to cyclic AMP. |
| Major function | Sequence-specific recognition of CRE promoter elements by CREB-family transcription factors to mediate cAMP-responsive transcription. |
| Representative binders | CREB1, CREM, ATF1 and related basic leucine zipper proteins. |
| Key coactivator | CBP (CREB-binding protein), which is recruited to phosphorylated CREB at CRE-containing promoters. |
| Regulatory modification | Phosphorylation of CREB at activating residues, which is required for efficient CRE-dependent transcription. |
What Is GO:0035497?
In practical terms, GO:0035497 describes the ability of a protein to bind a CRE DNA element. The CRE is a short palindrome-containing sequence present in the promoters of cAMP-responsive genes, and binding to this element is the first step in assembling a transcription-regulatory complex that changes the expression of the downstream gene. The function is therefore a sequence-specific DNA-binding activity rather than a catalytic activity, and it is typically studied by promoter-reporter assays, electrophoretic mobility shift assays and chromatin-based methods.
Why Is cAMP response element binding Important in Cell Biology?
cAMP response element binding is important because it links extracellular signals that raise cAMP to defined changes in gene expression. This function underlies the transcriptional response to many hormones and neurotransmitters and is required for normal circadian, neuronal and metabolic gene regulation. Because the same CRE-binding machinery is used in many cell types, its dysregulation has been implicated in diseases ranging from neurodegeneration to diabetic nephropathy and cancer.
• It converts cAMP signaling into transcription of CRE-containing target genes.
• It controls circadian clock gene expression, including Per1 induction in vivo.
• It regulates neuronal gene programs and has been linked to neurodegeneration.
• It is required for human TPH2 gene expression and serotonin biosynthesis.
• It contributes to kidney podocyte injury in diabetic nephropathy through target lncRNA regulation.
• It is a druggable node because CREB phosphorylation and dephosphorylation modulate its activity.
• It can be studied directly by CRISPR/Cas9 editing of CRE elements in target promoters.
• It provides a model for understanding how a short promoter element can integrate multiple signaling inputs.
Molecular Mechanism of cAMP response element binding
Recognition of the CRE palindrome
In simple terms: The CRE-binding protein reads a short symmetric DNA sequence in the promoter.
CREB-family proteins bind the CRE as dimers, using their basic leucine zipper domains to contact the palindrome-containing sequence in cAMP-responsive promoters. This sequence-specific recognition is the defining event of GO:0035497 and positions the transcription factor at the correct promoter.
Phosphorylation-dependent activation
In simple terms: A chemical tag on the CRE-binding protein turns it into an active transcription factor.
CREB is activated by phosphorylation at specific residues, and this phosphorylation is required for efficient CRE-dependent transcription. Activity-regulated phosphorylation of CREB has been observed in the developing striatum, where it is implicated in patterning neurochemical phenotypes.
Coactivator recruitment
In simple terms: Once bound, the protein recruits helper proteins that switch the gene on.
Phosphorylated CREB recruits the coactivator CBP (CREB-binding protein), which is a central component of the CRE transcriptional complex. Computational and structural studies of CBP have clarified how this coactivator interfaces with CREB and other transcription factors.
Target gene activation
In simple terms: The bound complex increases transcription of the downstream gene.
CRE binding leads to transcription of target genes such as Per1 in the circadian system and TPH2 in serotonin-producing cells. In the kidney, CREB-mediated transcription of the lncRNA DLX6-AS1 contributes to podocyte injury in diabetic nephropathy.
Modulation by CREM and related factors
In simple terms: Related proteins can tune or oppose the same CRE-binding function.
CREM, a CREB-family member, has roles in spermatogenesis and male fertility, illustrating that CRE-binding activity is diversified across family members. This diversification allows different cell types to use CRE elements for distinct transcriptional outcomes.
Key Genes Involved in GO:0035497 cAMP response element binding
The following genes and proteins are directly associated with cAMP response element binding and its downstream biology.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CREB1 | Core CRE-binding transcription factor | Central to cAMP-responsive transcription and neuronal gene regulation |
| CREM | CREB-family CRE-binding factor | Implicated in spermatogenesis and male fertility |
| ATF1 | CREB-family transcription factor | Contributes to CRE-dependent transcription |
| CBP (CREBBP) | CREB-binding coactivator | Recruited to phosphorylated CREB at CRE promoters |
| Per1 | Circadian target gene | Induced by CRE in vivo |
| TPH2 | Serotonin biosynthesis gene | Requires CRE-mediated transcription by CREB |
| DLX6-AS1 | lncRNA target in kidney | Mediates CREB-dependent podocyte injury |
| FLT1 | CRE/ETS-regulated gene | CRE mutation suppresses FLT1 expression |
| ETS factors | Adjacent promoter regulators | Cooperate with CRE in FLT1 regulation |
| CREB phosphorylation kinases | Upstream regulators | Control CREB activation state |
| CREB phosphatases | Upstream regulators | Oppose CREB phosphorylation |
| Striatal CREB targets | Neurochemical phenotype genes | Linked to striatal patterning |
| Podocyte CREB targets | Kidney injury genes | Linked to diabetic nephropathy |
| Circadian CREB targets | Clock genes | Linked to Per1 regulation |
| Serotonergic CREB targets | TPH2 pathway genes | Linked to serotonin biosynthesis |
| CREB-family dimers | DNA-binding complexes | Recognize the CRE palindrome |
| CBP-associated complexes | Chromatin-modifying coactivators | Enable CRE-dependent transcription |
How Is cAMP response element binding Regulated?
CRE binding is regulated by the phosphorylation state of CREB-family proteins. Activating phosphorylation promotes CRE-dependent transcription, while dephosphorylation opposes it, making kinases and phosphatases key upstream regulators. Activity-regulated phosphorylation of CREB in the developing striatum further shows that this regulation is context-dependent and developmental-stage-specific. In addition, coactivator availability, exemplified by CBP, modulates the efficiency of CRE-driven transcription.
cAMP response element binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CREB1 | Neurodegeneration | Neuronal knockout or point-mutation models |
| CREB1 | Diabetic nephropathy | Podocyte-specific knockout or overexpression |
| DLX6-AS1 | Kidney podocyte injury | lncRNA knockout or overexpression in podocytes |
| FLT1 | Angiogenesis-related gene regulation | CRISPR mutation of CRE and ETS sites |
| Per1 | Circadian rhythm | CRE knock-in reporter or knockout |
| TPH2 | Serotonin biosynthesis | CRE-driven reporter and CREB knockout |
Neurodegeneration
Phosphorylation- and dephosphorylation-dependent regulation of CREB has therapeutic implications in neurodegeneration, where altered CRE-dependent transcription contributes to neuronal dysfunction. Developmental regulation of CREB phosphorylation in the striatum further links this function to neurochemical phenotype patterning.
Diabetic nephropathy
CREB mediates podocyte injury in diabetic nephropathy by targeting the lncRNA DLX6-AS1, identifying CRE-dependent transcription as a disease-relevant mechanism in the kidney.
Cancer and angiogenesis-related gene control
CRISPR/Cas9-mediated mutation of a CRE and an adjacent ETS-binding site suppresses FLT1 gene expression, showing that CRE binding can be required for expression of genes involved in angiogenesis and cancer biology.
Circadian and neuropsychiatric biology
CRE-mediated induction of Per1 in vivo connects CRE binding to circadian clock regulation, while CRE-dependent TPH2 expression links it to serotonin biosynthesis and related neuropsychiatric processes.
From cAMP response element binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is CREB1 required for CRE-dependent target gene expression? | CREB1 knockout cell line |
| Does a specific CRE residue control promoter activity? | Point-mutated CRE knock-in |
| Can CRE-driven transcription be monitored in live cells? | CRE-luciferase or fluorescent knock-in reporter |
| Does CREB phosphorylation state determine target gene output? | Phospho-mutant knock-in |
| Is a CRE element necessary for FLT1 expression? | CRISPR/Cas9 mutation of CRE and ETS sites |
| Does CREB overexpression drive podocyte injury genes? | CREB overexpression in podocytes |
How to Study the cAMP response element binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRE-luciferase reporter | CRE-dependent transcriptional activity | Testing cAMP responsiveness of a promoter |
| CRISPR/Cas9 promoter editing | Requirement of a CRE for gene expression | Mutating CRE and ETS sites in FLT1 |
| Phospho-CREB immunoblot | Activation state of CREB | Neurodegeneration and striatal development studies |
| qRT-PCR of target genes | Expression of CRE-regulated genes | Per1, TPH2 and DLX6-AS1 analysis |
| Chromatin immunoprecipitation | Occupancy of CREB at CRE elements | Promoter binding studies |
| Coactivator interaction assays | CBP-CREB complex formation | Mechanistic studies of CRE transcription |
| Knockout cell models | Loss-of-function effects on CRE targets | CREB1 and CREM functional studies |
| Overexpression models | Gain-of-function effects on CRE targets | Podocyte injury and CREB target activation |
Promoter-reporter assays
CRE-driven reporter constructs are used to measure whether a candidate CRE mediates cAMP-responsive transcription, as shown for CRE-dependent Per1 induction and TPH2 expression.
CRISPR/Cas9 promoter editing
CRISPR/Cas9-mediated mutations in a CRE and an adjacent ETS-binding site suppress FLT1 gene expression, demonstrating that targeted editing can test the requirement for a specific CRE in a native promoter.
Phosphorylation analysis
Because CREB activity depends on phosphorylation and dephosphorylation, phospho-specific detection of CREB is a standard readout for CRE-binding function in cells and tissues.
Expression profiling of CRE targets
Measuring target genes such as Per1, TPH2 and DLX6-AS1 by quantitative expression methods links CRE binding to downstream transcriptional outputs in circadian, serotonergic and kidney contexts.
How CRISPR Can Be Used to Study GO:0035497 cAMP response element binding
Knockout
CRISPR knockout of CREB1 or CREM can be used to test whether CRE-dependent target gene expression requires a specific CRE-binding protein, as suggested by loss-of-function studies of CREB-family factors.
Point Mutation
Point mutation of the CRE palindrome or of CREB phosphorylation sites allows precise testing of which residues are required for CRE binding and activation, building on evidence that CREB phosphorylation is functionally important.
Knock-in
Knock-in of a reporter or tag at a CRE-regulated locus enables monitoring of CRE-dependent transcription in native chromatin, complementing reporter assays for Per1 and TPH2.
Overexpression
Overexpression of CREB or CREM can drive CRE-dependent target genes and model gain-of-function states such as podocyte injury mediated by DLX6-AS1.
How EDITGENE Supports cAMP response element binding Research
Researchers studying cAMP response element binding-related genes often need to determine whether a candidate gene is causally involved in a CRE-dependent transcriptional program. EDITGENE provides CRISPR-based cell models and screening services that allow this question to be addressed directly in relevant cell types.
Contact EDITGENE today to design your custom CRISPR model for cAMP response element binding research.
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| JUN Knockout HEK293 Cell Line | EDJ-KQ176 | Human | 3725 | Details Get a Quote |
| JUN Knockout HEK293T Cell Line | EDJ-KQ184 | Human | 3725 | Details Get a Quote |
| ATF2 Knockout HEK293 Cell Line | EDJ-KQ610 | Human | 1386 | Details Get a Quote |
| ATF4 Knockout HEK293 Cell Line | EDJ-KQ611 | Human | 468 | Details Get a Quote |
| CREB1 Knockout HEK293 Cell Line | EDJ-KQ781 | Human | 1385 | Details Get a Quote |
| CREB3L1 Knockout HEK293 Cell Line | EDJ-KQ783 | Human | 90993 | Details Get a Quote |
| CREB3L2 Knockout HEK293 Cell Line | EDJ-KQ784 | Human | 64764 | Details Get a Quote |
| CREB5 Knockout HEK293 Cell Line | EDJ-KQ787 | Human | 9586 | Details Get a Quote |
| HMGA2 Knockout HEK293 Cell Line | EDJ-KQ924 | Human | 8091 | Details Get a Quote |
| TCF12 Knockout HEK293 Cell Line | EDJ-KQ2699 | Human | 6938 | Details Get a Quote |
| NR4A3 Knockout HEK293 Cell Line | EDJ-KQ6158 | Human | 8013 | Details Get a Quote |
| JDP2 Knockout HEK293 Cell Line | EDJ-KQ8167 | Human | 122953 | Details Get a Quote |
| ATF2 Knockout HeLa Cell Line | EDJ-KQ18041 | Human | 1386 | Details Get a Quote |
| ATF4 Knockout A-549 Cell Line | EDJ-KQ18171 | Human | 468 | Details Get a Quote |
| ATF2 Knockout A-549 Cell Line | EDJ-KQ19068 | Human | 1386 | Details Get a Quote |
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Frequently Asked Questions About cAMP response element binding
What is cAMP response element binding?
cAMP response element binding is the molecular function GO:0035497, defined as binding to a cyclic AMP response element (CRE), a short palindrome-containing promoter sequence that mediates cAMP-responsive transcription.
What genes are involved in cAMP response element binding?
The main genes are CREB1, CREM and ATF1, together with the coactivator CBP (CREBBP) and target genes such as Per1, TPH2 and DLX6-AS1.
What is the GO ID for cAMP response element binding?
The GO ID is GO:0035497, and its ontology aspect is molecular_function.
How is CREB activated at cAMP response elements?
CREB is activated by phosphorylation at specific residues, and this phosphorylation is required for efficient CRE-dependent transcription.
What diseases are linked to cAMP response element binding?
It has been linked to neurodegeneration, diabetic nephropathy and angiogenesis-related gene regulation, among other conditions.
How can CRISPR be used to study cAMP response element binding?
CRISPR/Cas9 can mutate CRE elements or CREB phosphorylation sites, and CRISPR knockout can remove CREB-family factors to test their requirement for target gene expression.
What is the role of CBP in cAMP response element binding?
CBP is a CREB-binding coactivator that is recruited to phosphorylated CREB and is required for efficient CRE-dependent transcription.
Which target genes are regulated by CRE binding?
Examples include Per1 in the circadian system, TPH2 in serotonin biosynthesis and DLX6-AS1 in kidney podocyte injury.
Is CREM involved in cAMP response element binding?
Yes, CREM is a CREB-family CRE-binding factor with roles in spermatogenesis and male fertility.
How do I choose a model to study cAMP response element binding?
The choice depends on the question: knockout for loss-of-function, point mutation for residue-level analysis, knock-in for native-locus monitoring and overexpression for gain-of-function studies.
Conclusion
GO:0035497 cAMP response element binding is a sequence-specific DNA-binding function that converts cAMP signaling into defined transcriptional outputs. Its core machinery, the CREB-family factors and CBP coactivator, is used across circadian, neuronal, metabolic and kidney contexts, and its dysregulation is implicated in neurodegeneration, diabetic nephropathy and cancer-related gene control. CRISPR-based knockout, point-mutation, knock-in and overexpression models provide direct ways to test how CRE binding controls specific target genes in health and disease.
References
- 1. Ikegami K et al.. 2020. cAMP response element induces Per1 in vivo.. Biochem Biophys Res Commun 531(4):515-521 PMID: 32807491
- 2. Khakha N et al.. 2023. Therapeutic implications of phosphorylation- and dephosphorylation-dependent factors of cAMP-response element-binding protein (CREB) in neurodegeneration.. Pharmacol Rep 75(5):1152-1165 PMID: 37688751
- 3. Zheng W et al.. 2022. cAMP-response element binding protein mediates podocyte injury in diabetic nephropathy by targeting lncRNA DLX6-AS1.. Metabolism 129:155155 PMID: 35093327
- 4. Nawa Y et al.. 2025. cAMP-Response Element (CRE)-Mediated Transcription by CRE-Binding Protein (CREB) Is Essential for Human Tryptophan Hydroxylase 2 Gene Expression.. J Neurochem 169(6):e70138 PMID: 40542553
- 5. Akinsiku OE et al.. 2021. Update and Potential Opportunities in CBP [Cyclic Adenosine Monophosphate (cAMP) Response Element-Binding Protein (CREB)-Binding Protein] Research Using Computational Techniques.. Protein J 40(1):19-27 PMID: 33394237
- 6. Sánchez-Jasso DE et al.. 2023. Novel Aspects of cAMP-Response Element Modulator (CREM) Role in Spermatogenesis and Male Fertility.. Int J Mol Sci 24(16) PMID: 37628737
- 7. Sasagawa T et al.. 2023. CRISPR/Cas9-mediated mutations in both a cAMP response element and an ETS-binding site suppress FLT1 gene expression.. Exp Cell Res 424(1):113500 PMID: 36720378
- 8. Liu F et al.. 1998. Activity-regulated phosphorylation of cAMP response element binding protein in the developing striatum: implications for patterning the neurochemical phenotypes of striatal compartments.. Dev Neurosci 20(2-3):229-36 PMID: 9691196
