Affinage

CREM

cAMP-responsive element modulator · UniProt Q03060

Length
345 aa
Mass
37.0 kDa
Annotated
2026-04-28
100 papers in source corpus 39 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CREM is a modular bZIP transcription factor that generates functionally antagonistic isoforms—repressors and activators—through cell-specific alternative splicing, alternative promoter usage, and regulated polyadenylation, enabling it to serve as a master switch governing cAMP-responsive gene expression in spermatogenesis, circadian rhythmicity, immune cell function, and cardiac physiology (PMID:1847666, PMID:1370576, PMID:8252624, PMID:8397338, PMID:8600390). Repressor isoforms (CREMα/β/γ and the cAMP-inducible ICER) compete with CREB at CRE and TRE sites to antagonize transcription and create negative autoregulatory feedback loops that mediate hormonal desensitization and circadian oscillations, while in T cells CREMα recruits DNMT3a and G9a to epigenetically silence target loci such as the CD8 cluster (PMID:8252624, PMID:1429597, PMID:24297179). The activator isoform CREMτ, induced in postmeiotic germ cells by FSH-driven alternative splicing, is phosphorylated at Ser117 by PKA and other kinases to recruit CBP, but can also bypass phosphorylation-dependent activation through association with the testis-specific LIM-only coactivator ACT and the general transcription factor TFIIA, driving expression of spermiogenesis genes whose loss in CREM-null mice causes complete postmeiotic arrest and male infertility (PMID:8114765, PMID:10086359, PMID:14512522, PMID:8600390). CREM deletion also enhances CAR-NK cell effector function through epigenetic reprogramming, identifying CREM as a negative regulator of immune cytotoxicity (PMID:40468083).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1991 High

    The discovery that a single gene generates multiple CRE-binding repressor isoforms via alternative splicing established CREM as an antagonist of cAMP-induced transcription, revealing that the cAMP pathway has a dedicated transcriptional brake distinct from CREB.

    Evidence PCR, RNase protection, DNA binding assays, and reporter assays characterizing CREM isoforms and their repressor activity on CRE-driven promoters

    PMID:1647033 PMID:1847666

    Open questions at the time
    • Activator isoforms not yet identified
    • In vivo relevance of repression not demonstrated
    • Structural basis of repressor vs. activator function unknown
  2. 1992 High

    Identification of CREMτ as an activator isoform and demonstration that a developmental splicing switch converts CREM from repressor to activator during spermatogenesis revealed how a single locus can toggle between opposing transcriptional outputs in a tissue-specific manner.

    Evidence RT-PCR, Northern blot, and reporter assays showing stage-specific CREMτ accumulation in postmeiotic germ cells; separate demonstration that CREM repressors bind TRE sites to inhibit Jun-mediated transcription

    PMID:1370576 PMID:1429597

    Open questions at the time
    • Upstream signal driving the splicing switch unknown
    • Target genes of CREMτ in spermatids not identified
    • Mechanism by which CREMτ activates transcription not resolved
  3. 1993 High

    Multiple advances in 1993 defined the core activation mechanism: CREMτ is phosphorylated at Ser117 by PKA and other kinases to create a conditional activation domain (KID), ICER was identified as a cAMP-inducible autorepressive isoform from an intronic promoter, and circadian ICER oscillation was linked to adrenergic signaling in the pineal gland—together establishing the molecular logic of CREM's dual activator/autorepressor feedback circuit.

    Evidence In vitro kinase assays, in vivo phosphorylation labeling, domain-swap reporter assays, ICER promoter analysis, Northern blot time courses in pineal gland, pharmacological manipulation of adrenergic signaling

    PMID:8102791 PMID:8114763 PMID:8114765 PMID:8252624 PMID:8397338 PMID:8404858

    Open questions at the time
    • Coactivator recruited by phospho-KID not identified
    • Whether ICER feedback is sufficient for circadian rhythms not tested genetically
    • Contribution of casein kinases vs. PKA vs. cdc2 to CREM function in vivo unclear
  4. 1993 High

    FSH was identified as the pituitary hormone responsible for the CREMτ splicing switch in spermatogenesis, acting through alternative polyadenylation to stabilize CREMτ transcripts—connecting an endocrine axis to a post-transcriptional gene regulation event.

    Evidence Hypophysectomy abolishes CREMτ in testis; direct FSH administration restores it; seasonal spermatogenesis in hamsters as a natural model

    PMID:7681549

    Open questions at the time
    • Splicing factors mediating the FSH-driven switch not identified
    • Whether polyadenylation change is direct or indirect unknown
  5. 1994 High

    Structure–function studies showed that CREM's repressor versus activator output depends on modular domain composition and dimerization context: a minimal bZIP repressor lacking activation domains antagonizes CRE-driven transcription, while forced CREB–CREMα heterodimers can activate in a phosphorylation-dependent manner, demonstrating that dimer identity dictates functional outcome.

    Evidence Engineered leucine zipper domains to force defined dimer pairs, reporter assays, phosphorylation mutants; identification of spermatid-specific CREMδC-G repressor isoform

    PMID:7809053 PMID:7961842 PMID:8290258

    Open questions at the time
    • Crystal structure of CREM dimers not determined
    • Relative abundance of different dimers in vivo unknown
  6. 1996 High

    CREM knockout mice revealed that CREM is essential for spermiogenesis (complete postmeiotic arrest, loss of spermatozoa) and for circadian regulation of melatonin synthesis (derepression of NAT), establishing non-redundant in vivo functions for both the activator and ICER repressor arms.

    Evidence Homologous recombination knockout in two independent labs; histology, TUNEL, RT-PCR for target genes; ICER–CRE binding and NAT derepression in KO pineal

    PMID:8600390 PMID:8600391 PMID:8943074

    Open questions at the time
    • Which of the >6000 CREM-occupied loci are functionally required for spermiogenesis unknown
    • Redundancy with CREB in non-testis tissues not systematically tested
  7. 1996 High

    Demonstration that the balance between CREB and ICER at the CREM intronic promoter encodes photoperiod history ('circadian memory') revealed how the same autoregulatory loop can produce different transcriptional responses depending on prior light exposure.

    Evidence In vivo photoperiod manipulation with quantification of CREB vs. ICER protein levels and CREM transcriptional responsiveness

    PMID:8609995

    Open questions at the time
    • Chromatin state changes at the ICER promoter across photoperiods not examined
    • Whether this memory mechanism operates outside the pineal gland unknown
  8. 1998 High

    CREM was shown to coordinate hepatocyte proliferation timing after partial hepatectomy, with CREM-null mice exhibiting delayed S-phase entry and deregulated cyclin/cdc2 expression, extending CREM's functional repertoire beyond endocrine tissues to regenerative cell cycle control.

    Evidence Partial hepatectomy in CREM-/- mice with BrdU incorporation, histone H3 phosphorylation, RT-PCR for cell cycle genes

    PMID:9851970

    Open questions at the time
    • Direct vs. indirect regulation of cyclin genes by CREM not distinguished
    • Whether ICER or CREMτ mediates the hepatic phenotype unclear
  9. 1999 High

    Discovery of ACT, a testis-specific LIM-only coactivator that stimulates CREMτ transcription without requiring Ser117 phosphorylation or CBP, revealed a phosphorylation-independent activation pathway explaining how CREMτ can activate postmeiotic genes even in the absence of active PKA signaling.

    Evidence Yeast two-hybrid screen, co-immunoprecipitation, reporter assays in yeast and mammalian cells showing phosphorylation-independent activation

    PMID:10086359

    Open questions at the time
    • Structural basis of ACT–CREMτ interaction unknown
    • Whether ACT is the predominant coactivator in vivo or works alongside CBP unclear
  10. 1999 High

    CREB/CREM binding at the IL-2 promoter CRE was shown to mediate T cell anergy, establishing CREM as a regulator of adaptive immune tolerance and linking it to autoimmune pathology.

    Evidence EMSA supershift, site-directed mutagenesis of the -180 CRE in IL-2 reporter, anergy induction in T cells

    PMID:10586058

    Open questions at the time
    • Which CREM isoform predominates in anergic T cells not determined
    • In vivo contribution of CREM to anergy vs. other CRE-binding factors not resolved
  11. 2003 Medium

    Identification of TFIIA as a direct CREMτ-interacting partner in testis, and ICER-mediated repression of aromatase (CYP19) and TSH receptor, expanded the known cofactor repertoire and target gene landscape of CREM across reproductive and endocrine tissues.

    Evidence Two-hybrid screen, co-IP, co-localization in spermatocytes/spermatids for TFIIA; EMSA and reporter assays for ICER on CYP19 and TSH-R promoters

    PMID:14512522 PMID:14656211 PMID:7568187

    Open questions at the time
    • Functional consequence of TFIIA interaction for specific target gene expression not shown in vivo
    • Whether TFIIA and ACT cooperate or compete for CREMτ binding unclear
  12. 2005 High

    Identification of SRp40 as a splicing factor that regulates the CREM activator-to-repressor switch via exonic splicing enhancers provided the first molecular mechanism for tissue-specific CREM isoform choice outside the germline.

    Evidence Splicing factor overexpression, in vitro splicing, EMSA for SRp40-ESE binding, minigene analysis in human myometrial cells

    PMID:16103121

    Open questions at the time
    • Whether SRp40 also operates in testis or other tissues not tested
    • Upstream signals regulating SRp40 activity on CREM exons unknown
  13. 2006 High

    Demonstration that CREMτ heterodimerizes with Tisp40 to enhance CRE binding and recruit the histone chaperone HIRA added an epigenetic dimension to CREMτ's activation mechanism in spermatids.

    Evidence Co-IP, EMSA showing enhanced binding, ChIP confirming Tisp40 is a direct CREM target

    PMID:16595651

    Open questions at the time
    • Whether HIRA recruitment leads to specific histone variant deposition at CREMτ target genes not shown
    • Functional redundancy between ACT and Tisp40 pathways untested
  14. 2010 High

    Genome-wide ChIP-seq in round spermatids revealed that CREM occupies over 6700 loci—far exceeding the number of expression-dependent targets—indicating that CREM binding in spermatids occurs across broadly open chromatin and that occupancy alone is insufficient for transcriptional regulation.

    Evidence ChIP-seq in purified round spermatids with comparison to CREM-KO expression changes

    PMID:20920259

    Open questions at the time
    • What distinguishes functionally productive CREM binding from passive occupancy remains unknown
    • Cofactor co-occupancy at regulated vs. non-regulated sites not mapped
  15. 2013 High

    CREMα was shown to recruit DNMT3a and G9a to epigenetically silence the CD8 locus in SLE T cells, mechanistically explaining the expansion of pathogenic double-negative T cells and establishing CREM as an epigenetic effector in autoimmunity; separately, DAZAP1 was identified as a splicing regulator of CREM exon inclusion in testis.

    Evidence ChIP, co-IP, siRNA, flow cytometry in SLE T cells for epigenetic silencing; DAZAP1-null mouse and minigene assays for splicing

    PMID:23965306 PMID:24297179

    Open questions at the time
    • Whether CREMα recruits DNMT3a/G9a at other immune loci not tested genome-wide
    • Contribution of DAZAP1 vs. SRp40 to CREM splicing in different tissues not compared
  16. 2014 High

    CaMK4 was identified as an upstream kinase that activates CREMα to drive IL-17 transcription and Th17 differentiation, positioning CREM within the CaMK4–AKT/mTOR signaling axis relevant to SLE pathogenesis.

    Evidence CaMK4 knockout, pharmacological inhibition, siRNA in human SLE T cells, Th17 differentiation assays

    PMID:24667640

    Open questions at the time
    • Specific CREMα phosphorylation site(s) targeted by CaMK4 not mapped
    • Whether CaMK4–CREM axis operates in other Th subsets not examined
  17. 2016 High

    Transgenic cardiac expression of a CREM repressor isoform caused arrhythmogenic remodeling with action potential prolongation, early afterdepolarizations, and altered calcium handling, demonstrating that CREM repressor activity directly shapes cardiac electrophysiology.

    Evidence Transgenic mouse, patch clamp, calcium imaging, immunoblotting for NCX1, KChIP2, phospholamban

    PMID:26818679

    Open questions at the time
    • Which CREM target genes mediate the ion channel remodeling not identified by ChIP
    • Whether endogenous CREM repressor isoforms reach pathological levels in human heart disease unknown
  18. 2025 High

    CREM was identified as a negative regulator of CAR-NK cell cytotoxicity: CREM is induced downstream of CAR/ITAM and IL-15/PKA-CREB signaling, and its deletion enhances effector function and resistance to tumor-induced immunosuppression through epigenetic reprogramming, opening a new immunotherapy-relevant axis.

    Evidence CREM deletion by genetic editing in CAR-NK cells, in vitro cytotoxicity, in vivo tumor models, transcriptomic and epigenetic profiling

    PMID:40468083

    Open questions at the time
    • Specific epigenetic targets reprogrammed by CREM deletion in NK cells not fully characterized
    • Whether CREM also limits CAR-T cell function through similar mechanisms not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: what distinguishes functionally productive CREM occupancy from passive binding at the thousands of open-chromatin sites in spermatids; how the multiple coactivators (ACT, TFIIA, HIRA, CBP) are coordinated at specific target promoters; and whether the CREM-mediated epigenetic silencing mechanism discovered in SLE T cells operates genome-wide across immune cell subsets.
  • No structural model of CREMτ with any coactivator
  • Genome-wide cofactor co-occupancy map at CREM-bound sites lacking
  • Therapeutic targeting of specific CREM isoforms not achieved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 9 GO:0140110 transcription regulator activity 9
Localization
GO:0005634 nucleus 5
Partners
ACTCBPCREB1DNMT3AG9AHIRATFIIATISP40

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 CREM encodes multiple isoforms generated by cell-specific alternative splicing that use two alternative downstream DNA-binding domains; all isoforms bind CRE sequences with the same efficiency and specificity as CREB but act as transcriptional repressors/antagonists of cAMP-induced transcription rather than activators. PCR, RNase protection analysis, DNA binding assays, transfection reporter assays Cell High 1847666
1992 A developmental switch in CREM splicing occurs during spermatogenesis: premeiotic germ cells express CREM antagonist isoforms at low levels, whereas from pachytene spermatocyte stage onwards an alternative splicing event generates exclusively the CREM tau activator isoform (which contains two glutamine-rich activation domains) that accumulates to very high levels. Northern blot, RT-PCR, transfection reporter assays, cell-type-specific expression analysis Nature High 1370576
1991 CREM antagonists repress cAMP-induced c-fos transcription by binding to the CRE at -60 of the c-fos promoter and heterodimerizing with activator CREB; antisense CREM enhances c-fos basal and cAMP-induced transcription. CREM does not antagonize serum-induced transcription. Transfection reporter assays, antisense CREM expression, EMSA/competition binding Proceedings of the National Academy of Sciences of the United States of America High 1647033
1992 CREM antagonists bind TRE (AP-1) sites and competitively inhibit c-Jun transcriptional activation without heterodimerizing with Fos or Jun proteins; the phosphorylation domain of CREM is not required for this repression, and the Jun family members JunB, JunD, and v-Jun are also down-regulated. EMSA, transfection reporter assays, in vitro binding assays The Journal of biological chemistry High 1429597
1993 CREM is inducible by the cAMP signaling pathway from an alternative intronic promoter, generating the ICER (inducible cAMP early repressor) isoform as an early response gene. ICER binds to four tandem CREs in its own (intronic) promoter and represses its own transcription, constituting a negative autoregulatory feedback loop. The subsequent decline in CREM expression requires de novo protein synthesis. Promoter analysis, transfection reporter assays, Northern blot, protein synthesis inhibition experiments Cell High 8252624
1993 FSH (follicle-stimulating hormone) from the pituitary is responsible for the developmental CREM switch from antagonist to activator (CREM tau) during spermatogenesis; hypophysectomy extinguishes CREM tau expression in testis. FSH regulates CREM expression by alternative polyadenylation, resulting in enhanced transcript stability. Hypophysectomy experiments, seasonal spermatogenesis modulation in hamsters, direct hormone administration, Northern blot, RNase protection Nature High 7681549
1993 CREM tau is phosphorylated at Ser117 by protein kinase A (PKA) endogenous to germ cells, and this phosphorylation enhances its transactivation potential. CREM tau binds to CREs in promoters of postmeiotic germ cell-specific genes (e.g., RT7), and CREM-specific antibodies block RT7 in vitro transcription. In vitro kinase assays, transfection reporter assays, in vitro transcription with nuclear extracts, antibody supershift/blocking Molecular endocrinology (Baltimore, Md.) High 8114765
1993 The exon structure of the CREM gene was determined; CREM isoforms heterodimerize in vivo with each other and with CREB. The two alternative DNA-binding domains show distinct CRE binding efficiencies (CREM alpha/CREB heterodimers show stronger binding than CREM beta/CREB heterodimers). A phosphorylation domain plus a single glutamine-rich domain are sufficient for transcriptional activation. A minimal CREM repressor containing only the bZip motif efficiently antagonizes cAMP-induced transcription. Phosphorylation reduces repressor function. Exon mapping, in vivo dimerization assays, EMSA, transfection reporter assays, mutagenesis The EMBO journal High 8458330
1993 CREM tau is phosphorylated on multiple serine and threonine residues in vivo. Stimulation by forskolin, TPA, or Ca2+ ionophore enhances Ser117 phosphorylation and transactivation. Casein kinase I and II cooperatively phosphorylate CREM tau on multiple residues, enhancing DNA binding. Multiple kinases can phosphorylate Ser117 in vitro. In vivo phosphorylation labeling, in vitro kinase assays, EMSA, transfection reporter assays The EMBO journal High 8404858
1993 The CREM KID (kinase-inducible domain) containing Ser133-equivalent acts as a conditional activator that can enhance activity of other activation domains (Q2, GAL4, GCN4) via phosphorylation by PKA, even when attached to a separate polypeptide bound to an adjacent promoter site. CREM alpha and beta contain KID but function as repressors due to absence of activation domains. Transfection reporter assays with domain swaps and fusion proteins in mammalian cells Nature High 8102791
1993 Rhythmic adrenergic signals from the suprachiasmatic nucleus direct circadian ICER expression in the pineal gland via cAMP pathway stimulation, with ICER levels peaking at night and exhibiting a day-night fluctuation. RNase protection, Northern blot, pharmacological manipulation of adrenergic signaling in vivo Nature High 8397338
1993 p34cdc2 kinase phosphorylates CREM tau on multiple serine and threonine residues both in vivo and in vitro; coexpression of constitutively active p34cdc2 strongly reduces CREM tau trans-activation potential without affecting its DNA binding. In vivo and in vitro phosphorylation assays, EMSA, transfection reporter assays with constitutively active cdc2 mutant Molecular endocrinology (Baltimore, Md.) High 8114763
1994 DNA bending is induced by CREM (and CREB) binding to CRE flanking sequences. Phosphorylation of CREM or CREB enhances the angle of DNA bending. No differences in bending were detected between CREM proteins with the two alternative DNA-binding domains. Permuted binding site gel retardation assay with bacterially expressed proteins Oncogene Medium 8290258
1994 CREM alpha can form non-functional heterodimers with CREB that prevent gene activation, but when selectively forced into CREB-CREM alpha heterodimers via engineered leucine zippers, CREM alpha contributes to PKA-mediated gene activation in a phosphorylation-dependent manner. Thus the inhibitory function of CREM alpha depends on whether it is in a homodimer or heterodimer context and on phosphorylation state. Leucine zipper domain engineering to force defined dimer pairs, in vivo transcription assays The Journal of biological chemistry High 7961842
1994 A CREM isoform (CREM delta C-G) expressed in elongated spermatids lacks exons encoding the PKA phosphorylation domain and glutamine-rich activation domains but retains the bZIP DNA-binding domain; it binds CREs, competitively inhibits CREB and CREM CRE binding, and inhibits CRE-driven reporter transcription. RT-PCR from germ cells, EMSA, transfection reporter assays, immunostaining with CREM antiserum Proceedings of the National Academy of Sciences of the United States of America High 7809053
1995 TSH induces ICER (the inducible CREM isoform) in rat thyroid gland and FRTL-5 cells; ICER binds a CRE-like sequence in the TSH receptor (TSH-R) promoter and represses its expression. The kinetics of ICER induction mirrors TSH-R mRNA down-regulation, identifying ICER as a mediator of homologous long-term desensitization of the TSH receptor. Northern blot, EMSA, transfection reporter assays with ICER overexpression, in vivo TSH administration Proceedings of the National Academy of Sciences of the United States of America High 7568187
1995 A 111-bp first intron of the calspermin gene is required for CREM tau-mediated transcriptional enhancement via CRE motifs; deletion or inversion abolishes CREM tau stimulation; the intron functions as an orientation-dependent, position-independent regulatory element facilitating CREM tau activity. Deletion/inversion mutagenesis, footprinting, linker scanning, transfection reporter assays with CREM tau The Journal of biological chemistry High 7673120
1996 CREM-deficient mice (generated by homologous recombination) show postmeiotic arrest at the first step of spermiogenesis, complete absence of late spermatids, absence of spermatozoa, increased germ cell apoptosis (~10-fold), and loss of postmeiotic germ cell-specific gene expression. CREM is thus essential for spermiogenesis. Homologous recombination knockout, histology, TUNEL apoptosis assay, RT-PCR/Northern blot for target gene expression Nature High 8600390 8600391
1996 CREM-null mice show dramatic increase in serotonin N-acetyltransferase (NAT) expression in pineal gland. ICER binds a CRE site in the NAT promoter and represses NAT transcription in transfection assays, establishing CREM/ICER as a central regulator of circadian melatonin synthesis. CREM knockout mice, Northern blot, EMSA, transfection reporter assays Proceedings of the National Academy of Sciences of the United States of America High 8943074
1996 The transcriptional response of the CREM gene to adrenergic stimulation is modulated by prior photoperiod (circadian memory): the balance between positive regulator CREB and negative regulator ICER determines whether the CREM gene is subsensitive or supersensitive to cAMP induction depending on night length. In vivo photoperiod manipulation, Northern blot analysis, quantification of CREB vs. ICER levels Nature High 8609995
1998 CREM transcription factor coordinates hepatocyte proliferation timing after partial hepatectomy; CREM-/- mice show reduced DNA synthesis, fewer mitotic cells, delayed S-phase entry, and deregulated expression of cyclins A, B, D1, E, cdc2, c-fos, and tyrosine aminotransferase compared to wild-type. Partial hepatectomy in CREM-/- mice, BrdU incorporation, histone H3 phosphorylation, RT-PCR, immunostaining Genes & development High 9851970
1999 ACT (activator of CREM in testis), a LIM-only protein, was identified via two-hybrid screen as a testis-specific binding partner of CREM. ACT has intrinsic transcriptional activation function and strongly stimulates CREM transcriptional activity in yeast and mammalian cells in a phosphorylation-independent manner, bypassing the classical requirement for Ser117 phosphorylation and CBP interaction. Yeast two-hybrid screen, co-immunoprecipitation, transfection reporter assays in yeast and mammalian cells Nature High 10086359
1999 CREB/CREM complex binds the -180 site of the IL-2 promoter in anergic T cells; induction of anergy by prolonged TCR stimulation increases CREB/CREM binding at this site; mutation of the -180 site that specifically reduces CREB/CREM binding decreases susceptibility to anergy-induced IL-2 repression. EMSA, gel supershift assays, reporter constructs with site-specific mutations, T cell anergy induction Journal of immunology (Baltimore, Md. : 1950) High 10586058
1999 CREM-null mice show dramatically increased locomotion, equal locomotor activity throughout the circadian cycle (loss of circadian locomotor variation), and decreased anxiety-like behavior in two behavioral tests, demonstrating CREM's specific role in behavioral and circadian control. CREM-null mice, open field locomotor tests, anxiety behavioral models (elevated plus maze, light-dark box), circadian activity monitoring Proceedings of the National Academy of Sciences of the United States of America High 10570204
1999 CREMtau from germ cell nuclear extracts binds a conserved CYP51-CRE2 element in the CYP51 proximal promoter and activates CYP51 transcription in spermatids; CREM-/- mice lack abundant germ cell-specific CYP51 mRNAs while somatic CYP51 transcripts are unaffected, demonstrating CREM-dependent regulation of a cholesterogenic gene specifically in haploid germ cells. EMSA with germ cell vs. somatic nuclear extracts, CREM KO mice, Northern blot for CYP51 transcripts, promoter reporter assays Molecular endocrinology (Baltimore, Md.) High 10551787
2003 CREM interacts with the general transcription factor TFIIA (identified by two-hybrid screen from testis cDNA library and confirmed by co-immunoprecipitation); this interaction is restricted to activator isoforms of CREM and does not require Ser117 phosphorylation. CREM does not interact with testis-specific TFIIAtau-ALF. CREM and TFIIA colocalize in spermatocytes and spermatids. Yeast two-hybrid, co-immunoprecipitation, immunofluorescence co-localization Molecular endocrinology (Baltimore, Md.) Medium 14512522
2003 CREM-null mice display markedly depressed cardiac force-frequency relationship (reduced contractile augmentation and relaxation shortening at faster heart rates) associated with decreased total and serine-phosphorylated phospholamban protein and increased protein phosphatase-1 (PP1) activity, without changes in beta-adrenergic signaling, identifying a novel role for CREM in regulating PP1 activity and cardiac function. In vivo pressure-volume loops, echocardiography, PP1 activity assay, Western blot, isoproterenol dose-response in CREM-/- mice FASEB journal : official publication of the Federation of American Societies for Experimental Biology High 12554693
2005 SRp40, an SR protein splicing factor, regulates the switch in CREM alternative splicing from CREMtau2alpha (activator) to CREMalpha (repressor) in human myometrial cells during pregnancy; SRp40 acts through multiple exonic splicing enhancer (ESE) motifs in alternatively spliced CREM exons. Transient transfection of splicing factor constructs, in vitro splicing assays, EMSA for SRp40-ESE binding, minigene deletion analysis The Journal of biological chemistry High 16103121
2006 CREMtau and Tisp40 form a heterodimer that binds CRE (but not UPRE) elements; Tisp40 dramatically enhances the binding of CREMtau to CRE sequences. The Tisp40DeltaTM-CREMtau heterodimer recruits the histone chaperone HIRA to CRE sites. Tisp40alpha mRNA is a direct transcriptional target of CREM, as confirmed by ChIP. Co-immunoprecipitation, EMSA, ChIP, transfection reporter assays The Journal of biological chemistry High 16595651
2010 SPAG8 (sperm associated antigen 8), a testis-specific protein, associates with ACT (the CREM coactivator) and enhances ACT-mediated CREMtau transcriptional activation by strengthening ACT binding to CREMtau. Co-immunoprecipitation, pulldown assays, transfection reporter assays FEBS letters Medium 20488182
2010 ChIP-seq mapping in round spermatids shows CREM occupies more than 6700 genomic loci in a highly cell-specific manner, including promoters of spermiogenesis-specific genes and genes expressed in other cell types, indicating remarkably open chromatin in spermatids. Only a small subset of these occupied loci show expression changes in CREM knockout spermatids. Chromatin immunoprecipitation coupled to sequencing (ChIP-seq) in round spermatids; CREM KO comparison BMC genomics High 20920259
2011 A novel intronic CREM promoter (P2) upstream of exon 2 harbors functional TATA-box and AP-1 binding sites; T cell activation via CD3/CD28 or PMA/ionomycin enhances P2 promoter activity. In SLE T cells, reduced c-Fos content prevents AP-1-dependent P2 activation; CREM trans-represses c-fos, establishing an autoregulatory feedback between CREM and AP-1. DNA binding assays (EMSA), chromatin immunoprecipitation, reporter assays, siRNA, T cell stimulation assays The Journal of biological chemistry High 21757709
2013 CREMalpha orchestrates epigenetic silencing of the CD8 gene cluster in SLE T cells by recruiting DNA methyltransferase DNMT3a and histone methyltransferase G9a, driving expansion of CD3+CD4-CD8- double-negative T cells. Co-immunoprecipitation, ChIP, siRNA knockdown, flow cytometry, reporter assays The Journal of biological chemistry High 24297179
2013 DAZAP1 regulates alternative splicing of CREM pre-mRNA; DAZAP1 promotes inclusion of CREM exon 4 by binding regulatory sequences in CREM intron 3. Loss of DAZAP1 results in aberrant CREM splicing in mouse testis. Microarray exon profiling, splicing reporter minigene assays, DAZAP1 mutant binding studies, DAZAP1-null mouse model Nucleic acids research High 23965306
2014 CaMK4 is required for Th17 cell differentiation; CaMK4 activates CREMalpha, which in turn promotes IL-17 transcription and activates the AKT/mTOR pathway. Genetic or pharmacological inhibition of CaMK4 decreases CREMalpha activation, reducing IL17A and IL17F mRNA in human SLE T cells. Genetic CaMK4 knockout, pharmacological inhibition, siRNA in human and mouse T cells, Th17 differentiation assays, cytokine measurements, reporter assays The Journal of clinical investigation High 24667640
2016 Transgenic cardiac expression of CREM repressor isoform CREM-IbDeltaC-X leads to increased NCX-mediated Ca2+ transport, enhanced NCX1 protein levels, increased INCX, decreased Ito and KChIP2, action potential prolongation, increased early afterdepolarizations, and ventricular extrasystoles, demonstrating CREM repressor's role in arrhythmogenic cardiac remodeling. Patch clamp, calcium imaging, immunoblotting, RT-PCR, transgenic mouse model 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 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 deletion via genetic editing, in vitro cytotoxicity assays, in vivo tumor models, epigenetic profiling Nature High 40468083
2003 ICER (inducible CREM isoform) binds a CRE-like sequence in the CYP19 (aromatase) ovarian promoter; ICER overexpression suppresses FSH-induced CYP19 promoter activity in granulosa cells and R2C cells; stable antisense ICER blocks 24-48h cAMP-induced downregulation, identifying ICER/CREM as a mediator of LH-induced aromatase downregulation during luteinization. EMSA with supershift, transfection reporter assays, stable ICER overexpression and antisense cell lines The Journal of endocrinology High 14656211

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 485 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
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
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
1991 Transcriptional antagonist cAMP-responsive element modulator (CREM) down-regulates c-fos cAMP-induced expression. Proceedings of the National Academy of Sciences of the United States of America 109 1647033
1997 Cyclic AMP signalling and cellular proliferation: regulation of CREB and CREM. FEBS letters 98 9247115
2018 Molecular Profiling of Hyalinizing Clear Cell Carcinomas Revealed a Subset of Tumors Harboring a Novel EWSR1-CREM Fusion: Report of 3 Cases. The American journal of surgical pathology 91 29975250
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
1995 Thyroid-stimulating hormone (TSH)-directed induction of the CREM gene in the thyroid gland participates in the long-term desensitization of the TSH receptor. Proceedings of the National Academy of Sciences of the United States of America 85 7568187
1996 Adaptive inducibility of CREM as transcriptional memory of circadian rhythms. Nature 82 8609995
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
2019 Expanding the Phenotypic Spectrum of Mesenchymal Tumors Harboring the EWSR1-CREM Fusion. The American journal of surgical pathology 74 31305268
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
2013 cAMP responsive element modulator (CREM) α mediates chromatin remodeling of CD8 during the generation of CD3+ CD4- CD8- T cells. The Journal of biological chemistry 65 24297179
1998 CREM: a master-switch governing male germ cells differentiation and apoptosis. Seminars in cell & developmental biology 65 9813195
1997 Human endometrial stromal cells express novel isoforms of the transcriptional modulator CREM and up-regulate ICER in the course of decidualization. Molecular endocrinology (Baltimore, Md.) 64 8994192
2011 Abnormal methylation of the promoter of CREM is broadly associated with male factor infertility and poor sperm quality but is improved in sperm selected by density gradient centrifugation. Fertility and sterility 61 21507395
1995 Developmental maturation of pineal gland function: synchronized CREM inducibility and adrenergic stimulation. Molecular endocrinology (Baltimore, Md.) 61 8592516
1999 Altered emotional and locomotor responses in mice deficient in the transcription factor CREM. Proceedings of the National Academy of Sciences of the United States of America 60 10570204
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
2012 Novel insights into the downstream pathways and targets controlled by transcription factors CREM in the testis. PloS one 39 22384077
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
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
2005 Genetic control of spermiogenesis: insights from the CREM gene and implications for human infertility. Reproductive biomedicine online 37 15705296
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
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2000 CREM: a master-switch regulating the balance between differentiation and apoptosis in male germ cells. Molecular reproduction and development 34 10824972
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
2008 CREM modulates the circadian expression of CYP51, HMGCR and cholesterogenesis in the liver. Biochemical and biophysical research communications 29 18775413
2003 Transcriptional control in male germ cells: general factor TFIIA participates in CREM-dependent gene activation. Molecular endocrinology (Baltimore, Md.) 29 14512522
2025 CREM is a regulatory checkpoint of CAR and IL-15 signalling in NK cells. Nature 28 40468083
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
2010 Sperm associated antigen 8 (SPAG8), a novel regulator of activator of CREM in testis during spermatogenesis. FEBS letters 28 20488182
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
2004 Expression of activator of CREM in the testis (ACT) during normal and impaired spermatogenesis: correlation with CREM expression. Molecular human reproduction 27 14742698
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
2008 The role of transcription factors cyclic-AMP responsive element modulator (CREM) and inducible cyclic-AMP early repressor (ICER) in epileptogenesis. Neuroscience 25 18295410
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
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 24 34228212
2018 The transcription factor CREM drives an inflammatory phenotype of T cells in oligoarticular juvenile idiopathic arthritis. Pediatric rheumatology online journal 24 29925386
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
2012 Cyclic AMP response element modulator-1 (CREM-1) involves in neuronal apoptosis after traumatic brain injury. Journal of molecular neuroscience : MN 23 22569987
2003 The AmCREB gene is an ortholog of the mammalian CREB/CREM family of transcription factors and encodes several splice variants in the honeybee brain. Insect molecular biology 23 12864917
2021 Expression of Transcription Factor CREM in Human Tissues. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 22 34261344
2004 Specialized rules of gene transcription in male germ cells: the CREM paradigm. International journal of andrology 22 15595950
2022 Genetic inhibition of nuclear factor of activated T-cell c2 prevents atrial fibrillation in CREM transgenic mice. Cardiovascular research 21 34648001
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 Regulating the balance between differentiation and apoptosis: role of CREM in the male germ cells. Journal of molecular medicine (Berlin, Germany) 20 9846951
1995 An intron facilitates activation of the calspermin gene by the testis-specific transcription factor CREM tau. The Journal of biological chemistry 20 7673120
2023 Clear cell tumor with melanocytic differentiation and MITF::CREM translocation. Journal of cutaneous pathology 19 37057373
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
2017 Characterization of the Genetic Program Linked to the Development of Atrial Fibrillation in CREM-IbΔC-X Mice. Circulation. Arrhythmia and electrophysiology 19 28784605
2013 DAZAP1 regulates the splicing of Crem, Crisp2 and Pot1a transcripts. Nucleic acids research 19 23965306
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
2003 The inducible isoform of CREM (inducible cAMP early repressor, ICER) is a repressor of CYP19 rat ovarian promoter. The Journal of endocrinology 19 14656211
2023 Novel Aspects of cAMP-Response Element Modulator (CREM) Role in Spermatogenesis and Male Fertility. International journal of molecular sciences 18 37628737
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
2014 Upregulation of CREM/ICER suppresses wound endothelial CRE-HIF-1α-VEGF-dependent signaling and impairs angiogenesis in type 2 diabetes. Disease models & mechanisms 17 25381014
2008 Regulation of neural migration by the CREB/CREM transcription factors and altered Dab1 levels in CREB/CREM mutants. Molecular and cellular neurosciences 17 18786638
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
2018 Abnormal spermatogenesis following sodium fluoride exposure is associated with the downregulation of CREM and ACT in the mouse testis. Toxicology and industrial health 16 29529942
2017 CREM-transgene mice: An animal model of atrial fibrillation and thrombogenesis. Thrombosis research 16 28807377