Affinage

CREM

cAMP-responsive element modulator · UniProt Q03060

Length
345 aa
Mass
37.0 kDa
Annotated
2026-06-09
100 papers in source corpus 37 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CREM is a modular bZip transcription factor of the CRE-binding family that generates a spectrum of activator and repressor isoforms through alternative splicing, alternative promoter usage, and alternative polyadenylation, thereby acting as a versatile regulator of cAMP-responsive transcription across germ cells, neuroendocrine tissue, heart, liver, and immune cells (PMID:1847666, PMID:1370576, PMID:8458330). The earliest-defined isoforms are repressors that bind CRE sequences with the same specificity as CREB but down-regulate cAMP-induced transcription, and minimal bZip-only repressors compete with CREB/CREM for CRE and even TRE/AP-1 sites without requiring a phosphorylation domain (PMID:1847666, PMID:1429597, PMID:7809053). In testis a developmental splicing switch produces the activator CREMtau, which carries glutamine-rich activation domains and is phosphorylated at Ser-117 by PKA to enhance transactivation, while p34cdc2 phosphorylation conversely suppresses its activation potential (PMID:1370576, PMID:8404858, PMID:8114763); this switch is driven by FSH through alternative polyadenylation that stabilizes the transcript (PMID:7681549). CREMtau can also be activated independently of Ser-117 phosphorylation by the LIM-only coactivator ACT, whose nuclear availability is controlled by the testis kinesin KIF17b under PKA regulation (PMID:10086359, PMID:12493914, PMID:16002395). CREM is uniquely cAMP-inducible through an intronic promoter that drives the repressor ICER, which binds CREs in its own promoter to establish a negative autoregulatory feedback loop governing circadian melatonin synthesis in the pineal gland (PMID:8252624, PMID:8397338, PMID:8943074). Genetically, CREM is essential for spermiogenesis—knockout males are sterile with postmeiotic arrest and loss of germ-cell genes including CYP51 and testicular ACE (PMID:8600390, PMID:8600391, PMID:10551787, PMID:9545342)—and is required for hepatocyte cell-cycle timing during liver regeneration and for normal cardiac contractile gene expression (PMID:9851970, PMID:12475904). In T cells, CaMKIV/CaMK4-driven induction of CREMalpha represses IL-2 and activates IL-17A through recruitment of HDAC1 and DNMT3a and accompanying histone/DNA modifications, a pathway active in systemic lupus erythematosus and Th17 differentiation (PMID:15841182, PMID:22025620, PMID:21976679, PMID:24667640).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1991 High

    Established that CREM is not merely a CREB paralog but a dedicated repressor of cAMP-induced transcription, defining a built-in antagonist within the CRE-binding system.

    Evidence PCR, RNase protection, cell-specific splicing analysis and transcription assays defining repressor isoforms with two alternative DNA-binding domains

    PMID:1847666

    Open questions at the time
    • Did not explain how activator function could arise from the same gene
    • No in vivo physiological role yet defined
  2. 1992 High

    Showed the same gene can encode an activator (CREMtau) via alternative splicing of glutamine-rich domains and that a developmental antagonist-to-activator switch occurs during spermatogenesis, reframing CREM as a bifunctional regulator.

    Evidence Molecular cloning, functional transcription assays and developmental expression analysis in testis; plus DNA-binding competition showing repression of c-Jun/AP-1 by direct TRE binding

    PMID:1370576 PMID:1429597

    Open questions at the time
    • Upstream signal triggering the developmental switch not identified
    • How activator activity is regulated post-translationally unresolved
  3. 1993 High

    Resolved how CREMtau activity is tuned, identifying PKA phosphorylation at Ser-117 as activating and p34cdc2 phosphorylation as inhibitory, and dissected the modular exon/domain architecture that mixes DNA-binding, phosphorylation, and activation modules across isoforms.

    Evidence In vitro/in vivo phosphorylation and site-directed mutagenesis, p34cdc2 coexpression, domain deletion analysis, heterodimerization and DNA-binding assays

    PMID:8102791 PMID:8114763 PMID:8290258 PMID:8404858 PMID:8458330

    Open questions at the time
    • Phosphorylation-independent activation routes not yet known
    • Physiological kinases acting in vivo on each isoform incompletely mapped
  4. 1993 High

    Defined the FSH→CREM hormonal axis and the ICER autoregulatory loop, explaining how CREM becomes the only cAMP-inducible member of its family and how it self-limits via an intronic promoter.

    Evidence Hypophysectomy/hormone administration with polyadenylation and transcript-stability analysis (FSH); alternative intronic promoter cloning and ICER self-repression binding assays; circadian pineal expression analysis

    PMID:7681549 PMID:8252624 PMID:8397338

    Open questions at the time
    • Direct target genes of CREMtau in germ cells not yet identified
    • Tissue range of the ICER loop not fully delineated
  5. 1993 High

    Connected CREMtau to specific postmeiotic gene activation, providing the first direct target evidence for the testis activator.

    Evidence EMSA, transfection reporters, and antibody-blocked in vitro transcription from the RT7 promoter using seminiferous tubule nuclear extracts

    PMID:8114765

    Open questions at the time
    • Full set of postmeiotic targets unknown
    • In vivo requirement not yet tested genetically
  6. 1994 High

    Clarified heterodimer logic, showing CREMalpha contributes to PKA-dependent activation only when phosphorylatable, and identified a spermatid-specific bZip-only repressor isoform that competitively blocks CRE-driven transcription.

    Evidence Engineered leucine-zipper dimerization with PKA-dependent transcription readouts; RT-PCR, DNA-binding competition, reporter repression, and testis immunostaining

    PMID:7809053 PMID:7961842

    Open questions at the time
    • Endogenous partner preferences in vivo not quantified
    • Spatial coordination of activator vs repressor isoforms within tubules unclear
  7. 1996 High

    Demonstrated CREM is essential for male fertility, establishing a definitive in vivo function: spermiogenesis arrests with postmeiotic apoptosis and loss of germ-cell genes in knockout males.

    Evidence Homologous-recombination knockout mice with histology, TUNEL apoptosis assays, and germ-cell gene expression analysis

    PMID:8600390 PMID:8600391

    Open questions at the time
    • Molecular cause of apoptosis not fully resolved
    • Which isoforms drive the phenotype not separated genetically
  8. 1996 High

    Linked the ICER feedback loop to physiology, showing CREM/ICER governs circadian melatonin synthesis by repressing serotonin N-acetyltransferase, with photoperiod memory encoded by the CREB/ICER balance at the ICER promoter.

    Evidence CREM knockout mice, NAT promoter characterization, EMSA and reporter assays; photoperiod manipulation with promoter occupancy analysis

    PMID:8609995 PMID:8943074

    Open questions at the time
    • Mechanism integrating prior photoperiod into promoter occupancy not molecularly resolved
    • Other circadian CREM/ICER targets not catalogued
  9. 1998 High

    Extended CREM function to somatic proliferation, showing it is induced during liver regeneration and required for proper hepatocyte cell-cycle timing after partial hepatectomy.

    Evidence Partial hepatectomy in knockout vs wild-type mice with BrdU incorporation, histomorphometry, and cyclin/cdc2 expression analysis

    PMID:9851970

    Open questions at the time
    • Direct cell-cycle gene targets of CREM in hepatocytes not defined
    • Isoform responsible for proliferative role unidentified
  10. 1999 High

    Uncovered a phosphorylation-independent activation mechanism via the LIM-only coactivator ACT, explaining how CREMtau drives transcription in germ cells where PKA signaling may be limiting.

    Evidence Yeast two-hybrid screen, co-association and transcription assays in yeast and mammalian cells, phosphorylation-site mutant analysis

    PMID:10086359

    Open questions at the time
    • How ACT availability is controlled was unknown at this point
    • Structural basis of ACT-CREM interaction not defined
  11. 2000 Medium

    Generalized ACT into the FHL family of CBP-independent LIM coactivators for CREB/CREM and mapped LIM-domain arrangements required for transactivation and CREM binding.

    Evidence Yeast and mammalian transcription assays, deletion analysis, and tissue expression profiling

    PMID:11046156

    Open questions at the time
    • Single-lab functional data without structural validation
    • In vivo relevance of individual FHL proteins to CREM targets untested
  12. 2002 High

    Established that ACT nuclear availability—and hence CREM activation—is controlled by the testis kinesin KIF17b, whose CRM1-dependent nuclear export shuttles the coactivator.

    Evidence Reciprocal co-IP, immunofluorescence localization, leptomycin B perturbation, and stage-specific expression analysis

    PMID:12493914

    Open questions at the time
    • Signal triggering stage-specific KIF17b interaction not yet defined
    • Quantitative contribution of shuttling to target gene output unmeasured
  13. 2002 High

    Identified concrete germ-cell CREM targets and a cell-type-specific regulatory takeover, showing CREMtau replaces SREBP-1 at CYP51 and is absolutely required for testicular ACE expression.

    Evidence CREM knockout analysis, EMSA with germ-cell nuclear extracts, promoter reporters, and transgenic CRE-mutation reporter for ACET

    PMID:10551787 PMID:9545342

    Open questions at the time
    • Genome-wide germ-cell CREM target set still incomplete
    • Mechanism excluding SREBP-1 in germ cells not detailed
  14. 2002 High

    Revealed a cardiac role, showing CREM deficiency impairs contraction/relaxation with down-regulated beta1-adrenergic receptors and SERCA, identifying CREM as a regulator of cardiac gene expression.

    Evidence CREM knockout mice with hemodynamic assessment, beta-adrenergic stimulation, Western blot, and gene expression analysis

    PMID:12475904

    Open questions at the time
    • Direct cardiac CRE target promoters not individually validated
    • Isoform balance underlying the phenotype unresolved
  15. 2003 High

    Refined the cardiac mechanism, attributing the depressed force-frequency relationship to CREM-dependent control of phospholamban phosphorylation via altered PP1 activity rather than gene expression changes.

    Evidence CREM knockout mice with pressure-volume loops, frequency protocols, Western blot, and PP1 activity assays

    PMID:12554693

    Open questions at the time
    • How CREM controls PP1 activity mechanistically not defined
    • Transcriptional intermediary linking CREM to PP1 unidentified
  16. 2005 High

    Completed the germ-cell coactivator-trafficking circuit, showing PKA phosphorylation of KIF17b—through microtubule- and motor-independent transport—sets ACT nuclear availability and thus CREM activity.

    Evidence Domain-deletion mutants, microtubule depolymerization, in vitro PKA phosphorylation, and subcellular fractionation/localization

    PMID:16002395

    Open questions at the time
    • Mechanism of motor-independent transport unexplained
    • In vivo phenotype of disrupting KIF17b phosphorylation untested
  17. 2005 High

    Opened the immune axis, demonstrating that nuclear CaMKIV drives CREM upregulation and enhanced IL-2 promoter binding to suppress IL-2 in SLE T cells, with TCR-reactive autoantibodies as the upstream trigger.

    Evidence Dominant-negative CaMKIV overexpression, CREM promoter binding (EMSA/ChIP), IL-2 reporter assays in SLE patient T cells

    PMID:15841182

    Open questions at the time
    • Epigenetic mechanism of IL-2 silencing not yet defined at this stage
    • CREM isoform specificity in T cells not separated
  18. 2005 High

    Identified the splicing factor SRp40 as the controller of the CREM activator-to-repressor switch in pregnant myometrium, linking tissue physiology to isoform choice via exonic splicing enhancers.

    Evidence Splicing-factor transfection, in vitro splicing assays, SRp40 EMSA, and ESE mutagenesis

    PMID:16103121

    Open questions at the time
    • Signals controlling SRp40 activity in pregnancy not defined
    • Functional consequence for myometrial gene programs untested
  19. 2006 High

    Added a chromatin dimension to CREM activator function, showing CREMtau heterodimerizes with Tisp40 to recruit the histone chaperone HIRA at CREs and to autoregulate Tisp40 transcription.

    Evidence Co-IP, EMSA, ChIP, and reporter assays demonstrating reciprocal binding and HIRA recruitment

    PMID:16595651

    Open questions at the time
    • Functional outcome of HIRA recruitment on chromatin not assessed
    • Generality of Tisp40 partnership across tissues unknown
  20. 2011 High

    Defined the epigenetic mechanism of CREMalpha in T cells, showing it represses IL-2 via HDAC1/DNMT3a-mediated deacetylation and CpG hypermethylation while activating IL-17A through opposite epigenetic marks at its CRE.

    Evidence ChIP, bisulfite sequencing, siRNA knockdown, histone-modification and DNA-methylation analysis, and reporter assays in activated and SLE T cells

    PMID:21976679 PMID:22025620

    Open questions at the time
    • How a single factor recruits opposing complexes at different loci unresolved
    • In vivo contribution to autoimmunity not directly tested here
  21. 2011 High

    Mapped a second autoregulatory loop in T cells, identifying the AP-1-driven intronic P2 promoter that drives activation-induced CREM and a reciprocal CREM repression of c-fos.

    Evidence EMSA, ChIP, reporter assays, and T-cell stimulation experiments

    PMID:21757709

    Open questions at the time
    • Quantitative impact of P2 loop on CREM dosage in disease unclear
    • Interplay with the ICER loop not reconciled
  22. 2013 High

    Identified DAZAP1 as a splicing regulator promoting CREM exon 4 inclusion in testis, adding a germ-cell-specific layer to isoform control.

    Evidence Exon-usage microarrays, minigene splicing reporters, RNA-binding assays, and DAZAP1 knockout testis analysis

    PMID:23965306

    Open questions at the time
    • Functional consequence of altered CREM splicing for spermatogenesis not isolated
    • Coordination with SRp40/other factors unknown
  23. 2014 High

    Placed CREMalpha as the effector of CaMK4 in Th17 differentiation, showing CaMK4 inhibition reduces IL-17A/F production via decreased CREMalpha activation.

    Evidence CaMK4 knockout mice, pharmacological inhibition, Th17 differentiation assays, cytokine/mRNA analysis, and siRNA in human SLE and healthy T cells

    PMID:24667640

    Open questions at the time
    • Relative contribution of the AKT/mTOR arm vs CREMalpha not partitioned
    • In vivo therapeutic window not defined
  24. 2016 High

    Demonstrated that cardiac CREM repressor expression is arrhythmogenic, causing ion-channel remodeling and ventricular arrhythmia through suppression of CRE-dependent transcription.

    Evidence Transgenic CREM-IbDeltaC-X mice with patch clamp, calcium imaging, Western blot, RT-qPCR, and telemetry ECG

    PMID:26818679

    Open questions at the time
    • Direct CRE targets driving NCX1/KChIP2 changes not pinpointed
    • Relevance to endogenous CREM isoform balance in disease unclear
  25. 2025 High

    Extended CREM into innate immune-effector regulation, showing it is induced via PKA-CREB downstream of CAR/IL-15 signaling and restrains CAR-NK effector function through epigenetic reprogramming, making CREM deletion a route to enhanced anti-tumor activity.

    Evidence Transcriptomics, CREM knockout, in vitro/in vivo tumor models, PKA-CREB pathway inhibition, and epigenetic profiling

    PMID:40468083

    Open questions at the time
    • Specific CREM target loci in NK cells not enumerated
    • Isoform(s) responsible not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the genome-wide repertoire of CREM activator and repressor isoforms is dynamically balanced within a single cell to produce locus-specific activation versus epigenetic silencing remains unresolved.
  • No unified model linking isoform dosage to opposite epigenetic outcomes at different promoters
  • Structural basis for HDAC1/DNMT3a vs coactivator recruitment by the same factor undefined
  • Comprehensive in vivo target maps across tissues lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 9 GO:0003677 DNA binding 8 GO:0098772 molecular function regulator activity 4
Localization
GO:0005634 nucleus 5
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 5 R-HSA-4839726 Chromatin organization 4 R-HSA-8953854 Metabolism of RNA 3
Partners
ACT/FHL5CREB1DNMT3AHDAC1HIRAKIF17BTISP40

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 CREM encodes multiple isoforms (repressors) generated by alternative cell-specific splicing that use two alternative DNA-binding domains; CREM proteins bind CRE sequences with the same efficiency and specificity as CREB but act as down-regulators (antagonists) of cAMP-induced transcription. PCR, RNase protection, cell-specific splicing analysis, transcription assays Cell High 1847666
1992 A novel CREM isoform (CREM tau) expressed in adult testis contains two glutamine-rich activation domains inserted by alternative splicing and functions as a transcriptional activator rather than a repressor; during spermatogenesis, CREM undergoes a developmental switch from antagonist isoforms in premeiotic cells to the CREM tau activator from pachytene spermatocytes onwards. Alternative splicing analysis, functional transcription assays, developmental expression analysis in testis Nature High 1370576
1992 CREM antagonists repress c-Jun-mediated transcriptional activation not by heterodimerizing with Fos/Jun proteins, but by directly binding to TRE (AP-1) sequences and competing with c-Jun for these sites; removal of the phosphorylation domain from CREM does not affect this down-regulatory function. Transcription assays, DNA-binding competition, dimerization analysis, domain deletion mutants The Journal of biological chemistry High 1429597
1993 CREM is uniquely inducible within the CRE-binding family upon cAMP pathway activation; an alternative intronic promoter drives expression of a novel repressor isoform ICER (inducible cAMP early repressor); ICER binds to four CREs in its own intronic promoter and represses its own transcription, establishing a negative autoregulatory feedback loop. Alternative promoter cloning, kinetic induction analysis, protein synthesis inhibition, transfection reporter assays, ICER binding assays Cell High 8252624
1993 CREM tau activator is phosphorylated at serine-117 by endogenous germ cell protein kinase A; this phosphorylation enhances transcriptional activation. Casein kinase I and II cooperatively phosphorylate CREM tau on multiple residues to enhance DNA binding. Multiple signal transduction pathways (cAMP, TPA, Ca2+ ionophore) converge on phosphorylation of Ser-117. In vitro and in vivo phosphorylation assays, site-directed mutagenesis, DNA-binding assays, transactivation assays The EMBO journal High 8404858
1993 The CREM gene has a modular exon structure; isoforms are generated by exon shuffling producing proteins with various combinations of functional domains. CREM isoforms heterodimerize in vivo with each other and with CREB; the two alternative DNA-binding domains show distinct binding efficiencies (CREM alpha/CREB heterodimers bind consensus CRE more strongly than CREM beta/CREB heterodimers). The phosphorylation domain and a single glutamine-rich domain are sufficient for activation. A minimal CREM repressor containing only the bZip motif efficiently antagonizes cAMP-induced transcription. A Ser phosphoacceptor site mutation (CREM beta S68) increases repressor function. Exon structure determination, in vivo heterodimerization, in vitro DNA binding assays, domain deletion/mutation analysis, transcription assays The EMBO journal High 8458330
1993 FSH is responsible for directing the CREM developmental switch from antagonist to activator (CREM tau) in testis; FSH regulates CREM expression by alternative polyadenylation, which results in dramatic enhancement of transcript stability. Hypophysectomy abolishes CREM tau expression, and FSH administration restores it. Hypophysectomy, hormone administration, polyadenylation analysis, transcript stability measurement Nature High 7681549
1993 The KID (kinase-inducible domain) of CREB/CREM-alpha acts as a conditional activator that can confer cAMP-inducible transcriptional activation even to activation domains on a separate polypeptide bound at an adjacent promoter site, suggesting KID functions as a trans-acting conditional activator module. Domain fusion/swap transcription assays, artificial tethering experiments Nature Medium 8102791
1993 CREM tau activator is phosphorylated by p34cdc2 on multiple serine and threonine residues in vitro and in vivo; p34cdc2-mediated phosphorylation does not affect CREM tau DNA binding but strongly reduces its trans-activation potential (as shown by coexpression of constitutively active p34cdc2 mutant). In vitro and in vivo phosphorylation assays, constitutively active p34cdc2 coexpression, transactivation assays, DNA binding assays Molecular endocrinology High 8114763
1993 CREM tau binds to CREs in the promoters of several postmeiotic germ cell-specific genes (including RT7); CREM tau activates the RT7 promoter in transfection assays; CREM-specific antibodies block in vitro transcription from the RT7 promoter using seminiferous tubule nuclear extracts, directly implicating CREM tau in activating postmeiotic gene expression. EMSA, transient transfection reporter assays, in vitro transcription with antibody blockade, nuclear extracts from seminiferous tubules Molecular endocrinology High 8114765
1993 Rhythmic adrenergic signals from the circadian clock drive ICER expression in the pineal gland via the cAMP signal transduction pathway; ICER levels show striking circadian fluctuation (peak at night), correlating inversely with melatonin synthesis. In vivo circadian expression analysis, adrenergic stimulation, cAMP pathway activation Nature High 8397338
1994 An alternatively spliced CREM isoform (CREM delta C-G) lacking the PKA phosphorylation domain and glutamine-rich activation domains retains the bZip DNA-binding domain, competitively inhibits CREB/CREM binding to CREs, represses CRE-driven reporter transcription, and is expressed in elongated spermatids in rat testis. RT-PCR, DNA binding competition, reporter gene repression assays, immunostaining of testis sections PNAS High 7809053
1994 CREM alpha can contribute to PKA-mediated gene activation when selectively heterodimerized with CREB (using engineered leucine zipper specificity), and this transcriptional activity depends on the ability of the complexes to be phosphorylated by PKA; non-phosphorylated CREB.CREM alpha heterodimers are non-functional. Engineered leucine zipper dimerization, in vivo transcription assays, PKA phosphorylation The Journal of biological chemistry High 7961842
1994 CREM and CREB proteins induce bending in DNA sequences flanking the CRE recognition site; phosphorylation of CREM or CREB enhances the angle of DNA bending induced by these proteins, while not affecting binding affinity differences between the two alternative DNA-binding domains of CREM. Permutated binding site gel retardation assay (circular permutation), bacterially expressed proteins Oncogene Medium 8290258
1996 Homozygous CREM-mutant male mice (generated by homologous recombination) are sterile; spermatogenesis arrests at the first step of spermiogenesis with complete absence of late spermatids, a 10-fold increase in apoptotic germ cells, and lack of postmeiotic cell-specific gene expression. Female mice are fertile, confirming a male germ cell-specific essential function. Homologous recombination knockout, histology, TUNEL/apoptosis assays, gene expression analysis Nature High 8600390 8600391
1996 CREM-deficient mice show dramatically elevated serotonin N-acetyltransferase (NAT) expression in the pineal gland; the NAT promoter contains an ICER binding site; ICER powerfully represses NAT transcription in transfection assays; thus CREM/ICER acts as a central regulator of circadian melatonin synthesis. CREM knockout mice, promoter characterization, EMSA, transfection reporter assays PNAS High 8943074
1996 The transcriptional response of the CREM gene to adrenergic stimulation is determined by the memory of past photoperiods (night length); differential responsiveness is controlled by the changing balance between positive (CREB) and negative (ICER) transcriptional regulators occupying the ICER promoter. Photoperiod manipulation in vivo, adrenergic stimulation, CREM/ICER expression quantification, promoter occupancy analysis Nature High 8609995
1998 CREM gene expression is robustly induced during liver regeneration after partial hepatectomy; CREM-deficient mice show significantly reduced hepatocyte proliferation (reduced DNA synthesis, fewer mitoses, delayed S-phase entry, deregulated cyclin/cdc2 expression), demonstrating CREM is required for normal timing of the hepatocyte cell cycle after partial hepatectomy. Partial hepatectomy in CREM knockout vs. wild-type mice, BrdU incorporation, histomorphometry, gene expression analysis Genes & development High 9851970
1999 ACT (activator of CREM in testis), a LIM-only protein, specifically associates with CREM in male germ cells (isolated by yeast two-hybrid, confirmed by co-association); ACT has intrinsic transcriptional activation function and strongly stimulates CREM transcriptional activity independent of Ser-117 phosphorylation and CBP interaction, establishing a phosphorylation-independent route for CREM activation. Yeast two-hybrid screen, co-association assays, transcriptional activation assays in yeast and mammalian cells, phosphorylation-independent mutant analysis Nature High 10086359
2000 A family of FHL (four-and-a-half-LIM-domain) proteins share structural organization with ACT and provide CBP-independent transcriptional activation to both CREB and CREM in tissue-specific and developmentally regulated manner; specific ACT LIM domain arrangements are essential for both transactivation and interaction with CREM. Yeast and mammalian cell transcription assays, deletion analysis, tissue expression profiling Molecular and cellular biology Medium 11046156
2002 ACT selectively associates with testis-specific kinesin KIF17b; the ACT-KIF17b interaction is restricted to specific stages of spermatogenesis and directly determines the intracellular localization of ACT; KIF17b can be actively exported from the nucleus through the CRM1 receptor (leptomycin B-sensitive), thereby controlling CREM-dependent transcription in male germ cells through regulation of coactivator localization. Co-immunoprecipitation, subcellular localization (immunofluorescence), leptomycin B treatment, stage-specific expression analysis Science High 12493914
2002 CREM-null mice lack abundant germ cell-specific CYP51 mRNA transcripts in testis (while somatic CYP51 remains unaffected); CREMtau binds to a conserved CRE2 element in the CYP51 promoter in germ cell nuclear extracts, whereas SREBP-1 (the somatic regulator) does not bind in germ cells; thus CREMtau-dependent regulation of CYP51 is the dominant pathway in haploid germ cells, replacing the SREBP-dependent cholesterogenic regulation. CREM knockout analysis, EMSA with germ cell nuclear extracts, promoter reporter assays Molecular endocrinology High 10551787
2002 CREM is required for postmeiotic transcription of ACE testicular isozyme (ACET): ACET mRNA is absent from testes of CREM-null mice while pulmonary ACE remains unaffected; a CRE element 5' of the ACET transcription start site is absolutely essential for testicular expression (shown by transgenic reporter). CREM knockout mice, transgenic reporter analysis, CRE mutation The Journal of biological chemistry High 9545342
2002 CREM deficiency results in impaired cardiac contraction and relaxation, selective down-regulation of beta1-adrenergic receptors, and decreased ventricular SERCA (Ca2+-ATPase) expression; CREM-null mice show decreased responsiveness to beta-adrenergic stimulation, establishing CREM as a key regulator of cardiac gene expression required for normal contractile performance. CREM knockout mice, left ventricular hemodynamic assessment, beta-adrenergic stimulation, Western blot, gene expression analysis FASEB journal High 12475904
2003 CREM-null mice display markedly depressed cardiac force-frequency relationship (contractile augmentation and relaxation at faster rates); this is associated with reduced total and serine-phosphorylated phospholamban protein and increased protein phosphatase-1 (PP1) activity in CREM-/- hearts, without changes in SERCA or phospholamban gene expression or beta-adrenergic signaling, demonstrating novel CREM-dependent regulation of PP1 and PLB post-translational modification. CREM knockout mice, in vivo pressure-volume loops, frequency-dependent protocols, Western blot, PP1 activity assay FASEB journal High 12554693
2005 KIF17b transport of ACT is microtubule-independent and motor domain-independent; protein kinase A phosphorylates KIF17b, and this phosphorylation determines KIF17b's subcellular localization, thereby controlling CREM-mediated transcription in male germ cells through regulation of ACT nuclear availability. Domain deletion mutants, microtubule depolymerization assays, in vitro phosphorylation by PKA, subcellular fractionation/localization The Journal of biological chemistry High 16002395
2005 CaMKIV is increased in the nucleus of SLE T cells and is responsible for increased CREM expression and enhanced CREM binding to the IL-2 promoter (-180 CRE site), leading to decreased IL-2 production; expression of a dominant-inactive CaMKIV abolishes SLE-serum-induced CREM upregulation; anti-TCR/CD3 autoantibodies in SLE IgG are responsible for CaMKIV activation. Dominant-negative CaMKIV overexpression, CREM promoter binding assays (EMSA/ChIP), IL-2 promoter reporter assays, SLE patient T cells The Journal of clinical investigation High 15841182
2005 The splicing factor SRp40 mediates the switch in CREM alternative splicing in human myometrial cells from CREMtau2alpha (activator) to CREMalpha (repressor) during pregnancy; SRp40 acts through multiple ESE (exonic splicing enhancer) motifs in the alternatively spliced CREM exons. Transient transfection of splicing factors, in vitro splicing assays, EMSA with SRp40, ESE mutagenesis The Journal of biological chemistry High 16103121
2006 CREMtau and Tisp40 (a bZip transcription factor) form a heterodimer that binds CRE motifs (but not UPRE); Tisp40 dramatically enhances CREM binding to CRE; the Tisp40DeltaTM-CREMtau heterodimer recruits histone chaperone HIRA to CRE sites; CREM regulates Tisp40alpha transcription, and both proteins co-occupy the Tisp40 promoter in vivo (ChIP). Co-immunoprecipitation, EMSA, ChIP, reporter assays, in vivo binding The Journal of biological chemistry High 16595651
2011 CREMα physically binds to a CRE site at -111/-104 within the proximal human IL17A promoter and increases its transcriptional activity; CREMα binding correlates with epigenetic changes (H3K27 hypomethylation, H3K18 hyperacetylation, CpG hypomethylation) at the IL17A locus in activated T cells and SLE T cells; decreased HDAC1 and DNMT3a recruitment to this CRE site accounts for the epigenetic alterations. ChIP, reporter assays, DNA methylation analysis, histone modification analysis The Journal of biological chemistry High 22025620
2011 CREMα mediates silencing of the IL2 gene in SLE T lymphocytes through recruitment of HDAC1 leading to gene-wide H3K18 deacetylation and DNMT3a-mediated CpG-DNA hypermethylation at the IL2 gene locus. ChIP, bisulfite sequencing (CpG methylation), siRNA knockdown, reporter assays with methylated promoter The Journal of biological chemistry High 21976679
2011 A novel intronic CREM promoter (P2) upstream of exon 2 is regulated by AP-1 transcription factors; T cell activation via CD3/CD28 or PMA/ionomycin enhances P2 promoter activity; in SLE T cells, decreased c-Fos (an AP-1 component) impairs activation-induced CREM upregulation through P2; CREM trans-represses c-fos transcription in SLE T cells, establishing a CREM-AP-1 autoregulatory feedback loop. DNA binding studies (EMSA), ChIP, reporter assays, T cell stimulation experiments The Journal of biological chemistry High 21757709
2013 DAZAP1 promotes inclusion of CREM exon 4 in splicing reporter transcripts; DAZAP1 binds to regulatory regions in CREM intron 3 and regulates exon inclusion; DAZAP1-deficient mouse testes show aberrant CREM splicing, identifying DAZAP1 as a splicing regulator of CREM. Microarray exon usage analysis, minigene splicing reporters, RNA-binding assays, DAZAP1 knockout Nucleic acids research High 23965306
2014 CaMK4 is required for Th17 cell differentiation; CaMK4 activates CREMα which in turn increases IL17A and IL17F transcription; CaMK4 also activates the AKT/mTOR pathway. Genetic or pharmacological inhibition of CaMK4 reduces IL-17 production through decreased CREMα activation; silencing CaMK4 in SLE and healthy T cells inhibits Th17 differentiation via reduction of IL17A and IL17F mRNA. CaMK4 knockout mice, pharmacological inhibition, Th17 differentiation assays, cytokine measurement, mRNA analysis, siRNA in human T cells The Journal of clinical investigation High 24667640
2016 Transgenic cardiac expression of CREM repressor isoform CREM-IbΔC-X leads to arrhythmogenic alterations in ventricular cardiomyocytes including enhanced NCX-mediated Ca2+ transport, increased NCX1 protein, decreased Ito and KChIP2 subunit, action potential prolongation, early afterdepolarizations, and ventricular extrasystoles in vivo; CREM repressor expression suppresses CRE-dependent transcription to produce an arrhythmogenic remodeling substrate. Transgenic mouse model, patch clamp, calcium imaging, Western blot, RT-qPCR, telemetry ECG Basic research in cardiology High 26818679
2025 CREM is induced in CAR-NK cells by both CAR activation and IL-15 signaling via the PKA-CREB signaling pathway downstream of ITAM/CAR signaling; CREM deletion enhances CAR-NK cell effector function in vitro and in vivo and increases resistance to tumor-induced immunosuppression; CREM exerts its regulatory functions through epigenetic reprogramming of CAR-NK cells. Transcriptomic analysis, CREM knockout, in vitro and in vivo functional assays, pharmacological PKA-CREB pathway inhibition, epigenetic profiling Nature High 40468083

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1991 CREM gene: use of alternative DNA-binding domains generates multiple antagonists of cAMP-induced transcription. Cell 619 1847666
1993 Inducibility and negative autoregulation of CREM: an alternative promoter directs the expression of ICER, an early response repressor. Cell 518 8252624
1996 Spermiogenesis deficiency and germ-cell apoptosis in CREM-mutant mice. Nature 486 8600390
1996 Severe impairment of spermatogenesis in mice lacking the CREM gene. Nature 454 8600391
1992 Developmental switch of CREM function during spermatogenesis: from antagonist to activator. Nature 444 1370576
1993 Adrenergic signals direct rhythmic expression of transcriptional repressor CREM in the pineal gland. Nature 362 8397338
1999 Signaling routes to CREM and CREB: plasticity in transcriptional activation. Trends in biochemical sciences 241 10390618
1993 Pituitary hormone FSH directs the CREM functional switch during spermatogenesis. Nature 236 7681549
1993 Induction of CREM activator proteins in spermatids: down-stream targets and implications for haploid germ cell differentiation. Molecular endocrinology (Baltimore, Md.) 206 8114765
1993 The functional versatility of CREM is determined by its modular structure. The EMBO journal 202 8458330
2005 Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV. The Journal of clinical investigation 191 15841182
1999 CBP-independent activation of CREM and CREB by the LIM-only protein ACT. Nature 190 10086359
1992 Transcriptional cross-talk: nuclear factors CREM and CREB bind to AP-1 sites and inhibit activation by Jun. The Journal of biological chemistry 188 1429597
2014 CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance. The Journal of clinical investigation 183 24667640
2000 A family of LIM-only transcriptional coactivators: tissue-specific expression and selective activation of CREB and CREM. Molecular and cellular biology 181 11046156
1993 Multiple and cooperative phosphorylation events regulate the CREM activator function. The EMBO journal 180 8404858
1993 Protein-kinase-A-dependent activator in transcription factor CREB reveals new role for CREM repressors. Nature 153 8102791
2002 The expanding family of CREB/CREM transcription factors that are involved with spermatogenesis. Molecular and cellular endocrinology 150 11988318
2002 Coupling cAMP signaling to transcription in the liver: pivotal role of CREB and CREM. Experimental cell research 146 11969286
1996 Transcriptional control of circadian hormone synthesis via the CREM feedback loop. Proceedings of the National Academy of Sciences of the United States of America 130 8943074
1994 A complex array of positive and negative elements regulates the chicken alpha A-crystallin gene: involvement of Pax-6, USF, CREB and/or CREM, and AP-1 proteins. Molecular and cellular biology 129 7935450
2011 cAMP-responsive element modulator (CREM)α protein induces interleukin 17A expression and mediates epigenetic alterations at the interleukin-17A gene locus in patients with systemic lupus erythematosus. The Journal of biological chemistry 112 22025620
1997 Cyclic AMP signalling and cellular proliferation: regulation of CREB and CREM. FEBS letters 98 9247115
1995 A Drosophila CREB/CREM homolog encodes multiple isoforms, including a cyclic AMP-dependent protein kinase-responsive transcriptional activator and antagonist. Molecular and cellular biology 93 7651429
2002 CREM-dependent transcription in male germ cells controlled by a kinesin. Science (New York, N.Y.) 91 12493914
1999 The -180 site of the IL-2 promoter is the target of CREB/CREM binding in T cell anergy. Journal of immunology (Baltimore, Md. : 1950) 88 10586058
1998 Testicular cAMP responsive element modulator (CREM) protein is expressed in round spermatids but is absent or reduced in men with round spermatid maturation arrest. Molecular human reproduction 88 9510006
1993 Transcriptional response to cAMP in brain: specific distribution and induction of CREM antagonists. Neuron 87 8386526
1996 Adaptive inducibility of CREM as transcriptional memory of circadian rhythms. Nature 82 8609995
2019 Expanding the Phenotypic Spectrum of Mesenchymal Tumors Harboring the EWSR1-CREM Fusion. The American journal of surgical pathology 78 31305268
1994 An isoform of transcription factor CREM expressed during spermatogenesis lacks the phosphorylation domain and represses cAMP-induced transcription. Proceedings of the National Academy of Sciences of the United States of America 75 7809053
2011 cAMP-responsive element modulator (CREM)α protein signaling mediates epigenetic remodeling of the human interleukin-2 gene: implications in systemic lupus erythematosus. The Journal of biological chemistry 73 21976679
1999 Cyclic adenosine 3',5'-monophosphate(cAMP)/cAMP-responsive element modulator (CREM)-dependent regulation of cholesterogenic lanosterol 14alpha-demethylase (CYP51) in spermatids. Molecular endocrinology (Baltimore, Md.) 69 10551787
1996 Role of transcription factors CREB and CREM in cAMP-regulated transcription during spermatogenesis. Trends in endocrinology and metabolism: TEM 68 18406739
1998 CREM: a master-switch governing male germ cells differentiation and apoptosis. Seminars in cell & developmental biology 66 9813195
1998 Transcription factor CREM coordinates the timing of hepatocyte proliferation in the regenerating liver. Genes & development 58 9851970
2007 ICER/CREM-mediated transcriptional attenuation of IL-2 and its role in suppression by regulatory T cells. European journal of immunology 55 17372992
2010 Cell-specific occupancy of an extended repertoire of CREM and CREB binding loci in male germ cells. BMC genomics 54 20920259
2001 cAMP response element modulator (CREM): an essential factor for spermatogenesis in primates? International journal of andrology 53 11380701
1997 Cyclic AMP signalling pathway and cellular proliferation: induction of CREM during liver regeneration. Oncogene 52 9129151
1993 Human CREM gene: evolutionary conservation, chromosomal localization, and inducibility of the transcript. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 46 7916662
2006 Transcriptional regulation of the glucose-6-phosphatase gene by cAMP/vasoactive intestinal peptide in the intestine. Role of HNF4alpha, CREM, HNF1alpha, and C/EBPalpha. The Journal of biological chemistry 45 16893891
2000 CREM, a master-switch of the transcriptional cascade in male germ cells. Journal of endocrinological investigation 43 11079454
2006 Survival of DA neurons is independent of CREM upregulation in absence of CREB. Genesis (New York, N.Y. : 2000) 42 16981198
2021 Clear cell tumor with melanocytic differentiation and MITF-CREM translocation: a novel entity similar to clear cell sarcoma. Virchows Archiv : an international journal of pathology 41 33462743
2001 Transcriptional cascades during spermatogenesis: pivotal role of CREM and ACT. Molecular and cellular endocrinology 39 11420126
2013 Regulatory T-cells and cAMP suppress effector T-cells independently of PKA-CREM/ICER: a potential role for Epac. The Biochemical journal 38 24007532
2005 Genetic control of spermiogenesis: insights from the CREM gene and implications for human infertility. Reproductive biomedicine online 38 15705296
2004 PE-1/METS, an antiproliferative Ets repressor factor, is induced by CREB-1/CREM-1 during macrophage differentiation. The Journal of biological chemistry 38 14754893
2025 CREM is a regulatory checkpoint of CAR and IL-15 signalling in NK cells. Nature 37 40468083
2005 Microtubule-independent and protein kinase A-mediated function of kinesin KIF17b controls the intracellular transport of activator of CREM in testis (ACT). The Journal of biological chemistry 36 16002395
1996 Electroconvulsive seizure increases the expression of CREM (cyclic AMP response element modulator) and ICER (inducible cyclic AMP early repressor) in rat brain. Journal of neurochemistry 36 8522985
1996 CREM: a master-switch in the transcriptional response to cAMP. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 35 8735279
2000 CREM: a master-switch regulating the balance between differentiation and apoptosis in male germ cells. Molecular reproduction and development 34 10824972
2002 Impaired cardiac contraction and relaxation and decreased expression of sarcoplasmic Ca2+-ATPase in mice lacking the CREM gene. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 12475904
2000 CREM activator and repressor isoforms in human testis: sequence variations and inaccurate splicing during impaired spermatogenesis. Molecular human reproduction 32 11044457
1994 Modulatory function of CREB.CREM alpha heterodimers depends upon CREM alpha phosphorylation. The Journal of biological chemistry 32 7961842
2000 Induction of cAMP response element modulator (CREM) and inducible cAMP early repressor (ICER) expression in rat brain by uncompetitive N-methyl-D-aspartate receptor antagonists. The Journal of pharmacology and experimental therapeutics 31 10871295
2008 CREM modulates the circadian expression of CYP51, HMGCR and cholesterogenesis in the liver. Biochemical and biophysical research communications 29 18775413
2021 Intra-abdominal EWSR1/FUS-CREM-rearranged malignant epithelioid neoplasms: two cases of an emerging aggressive entity with emphasis on misleading immunophenotype. Virchows Archiv : an international journal of pathology 28 34228212
2011 A novel intronic cAMP response element modulator (CREM) promoter is regulated by activator protein-1 (AP-1) and accounts for altered activation-induced CREM expression in T cells from patients with systemic lupus erythematosus. The Journal of biological chemistry 28 21757709
2009 The CREB/CREM transcription factors negatively regulate early synaptogenesis and spontaneous network activity. The Journal of neuroscience : the official journal of the Society for Neuroscience 28 19144833
2000 Expression of the cyclic AMP-dependent transcription factors, CREB, CREM and ATF2, in the human myometrium during pregnancy and labour. Molecular human reproduction 28 10871653
2007 CREM deficiency in mice alters the response of bone to intermittent parathyroid hormone treatment. Bone 27 17275432
2004 Expression of activator of CREM in the testis (ACT) during normal and impaired spermatogenesis: correlation with CREM expression. Molecular human reproduction 27 14742698
1996 CREM: a transcriptional master switch during the spermatogenesis differentiation program. Frontiers in bioscience : a journal and virtual library 27 9159233
1994 DNA bending by transcription factors CREM and CREB. Oncogene 27 8290258
1993 Phosphorylation and negative regulation of the transcriptional activator CREM by p34cdc2. Molecular endocrinology (Baltimore, Md.) 26 8114763
2018 The transcription factor CREM drives an inflammatory phenotype of T cells in oligoarticular juvenile idiopathic arthritis. Pediatric rheumatology online journal 25 29925386
2000 The CREM system in human spermatogenesis. Journal of endocrinological investigation 25 11079452
1996 The nuclear response to cAMP: role of transcription factor CREM. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 25 8650267
2006 Transcription factors, cAMP-responsive element modulator (CREM) and Tisp40, act in concert in postmeiotic transcriptional regulation. The Journal of biological chemistry 24 16595651
2016 Cardiac expression of the CREM repressor isoform CREM-IbΔC-X in mice leads to arrhythmogenic alterations in ventricular cardiomyocytes. Basic research in cardiology 23 26818679
2022 Genetic inhibition of nuclear factor of activated T-cell c2 prevents atrial fibrillation in CREM transgenic mice. Cardiovascular research 22 34648001
2021 Expression of Transcription Factor CREM in Human Tissues. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 22 34261344
2012 Case-control association study of 14 variants of CREB1, CREBBP and CREM on diagnosis and treatment outcome in major depressive disorder and bipolar disorder. Psychiatry research 22 22386572
2004 Specialized rules of gene transcription in male germ cells: the CREM paradigm. International journal of andrology 22 15595950
2023 Clear cell tumor with melanocytic differentiation and MITF::CREM translocation. Journal of cutaneous pathology 20 37057373
2017 Transcription Factor CREM Mediates High Glucose Response in Cardiomyocytes and in a Male Mouse Model of Prolonged Hyperglycemia. Endocrinology 20 28368536
2013 Upregulation of CREM-1 relates to retinal ganglion cells apoptosis after light-induced damage in vivo. Journal of molecular neuroscience : MN 20 24166353
2005 CREM activator and repressor isoform expression in human male germ cells. International journal of andrology 20 16048633
2003 Novel regulation of cardiac force-frequency relation by CREM (cAMP response element modulator). FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20 12554693
2002 Novel leader exons of the cyclic adenosine 3',5'-monophosphate response element modulator (CREM) gene, transcribed from promoters P3 and P4, are highly testis-specific in primates. Molecular human reproduction 20 12397208
1998 A cyclic AMP response element in the angiotensin-converting enzyme gene and the transcription factor CREM are required for transcription of the mRNA for the testicular isozyme. The Journal of biological chemistry 20 9545342
1998 Regulating the balance between differentiation and apoptosis: role of CREM in the male germ cells. Journal of molecular medicine (Berlin, Germany) 20 9846951
2021 Clear Cell Odontogenic Carcinoma: First Report of Novel EWSR1-CREM Fusion Gene in Case of Long-Term Misdiagnosis. Head and neck pathology 19 33616852
2013 DAZAP1 regulates the splicing of Crem, Crisp2 and Pot1a transcripts. Nucleic acids research 19 23965306
2006 Sequencing and haplotype analysis of the activator of CREM in the testis (ACT) gene in populations of fertile and infertile males. Molecular human reproduction 19 16687568
2005 The switch in alternative splicing of cyclic AMP-response element modulator protein CREM{tau}2{alpha} (activator) to CREM{alpha} (repressor) in human myometrial cells is mediated by SRp40. The Journal of biological chemistry 19 16103121
2024 Extra-abdominal and intra-abdominal FET::CREM fusion mesenchymal neoplasms: comparative clinicopathological study of 9 new cases further supporting a distinct potentially aggressive sarcoma and report of novel sites. Virchows Archiv : an international journal of pathology 18 39249507
2023 Novel Aspects of cAMP-Response Element Modulator (CREM) Role in Spermatogenesis and Male Fertility. International journal of molecular sciences 18 37628737
2014 Upregulation of CREM/ICER suppresses wound endothelial CRE-HIF-1α-VEGF-dependent signaling and impairs angiogenesis in type 2 diabetes. Disease models & mechanisms 18 25381014
2008 Regulation of neural migration by the CREB/CREM transcription factors and altered Dab1 levels in CREB/CREM mutants. Molecular and cellular neurosciences 18 18786638
2020 Primary Intracranial Mesenchymal Tumor with EWSR1-CREM Gene Fusion: A Case Report and Literature Review. World neurosurgery 17 32668333
2017 Ventral striatal regulation of CREM mediates impulsive action and drug addiction vulnerability. Molecular psychiatry 17 28439100
2017 1,2-Dichloroethane Induces Reproductive Toxicity Mediated by the CREM/CREB Signaling Pathway in Male NIH Swiss Mice. Toxicological sciences : an official journal of the Society of Toxicology 17 28973639
2015 The cAMP response element modulator (CREM) regulates TH2 mediated inflammation. Oncotarget 17 26459392
2003 Human nuclear transcription factor gene CREM: genomic organization, mutation screening, and association analysis in panic disorder. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 17 12555239
2001 Cloning and expression of activator of CREM in testis in human testicular tissue. Biochemical and biophysical research communications 17 11327716
1995 The cyclic AMP response elements of the genes for angiotensin converting enzyme and phosphoenolpyruvate carboxykinase (GTP) can mediate transcriptional activation by CREM tau and CREM alpha. The Journal of biological chemistry 17 7642572

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