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FLASH GENE
Symbol CREM contributors: mct - updated : 19-02-2018
HGNC name cAMP responsive element modulator
HGNC id 2352
Location 10p11.21      Physical location : 35.415.800 - 35.501.885
Synonym name
  • cAMP-response element (CRE) binding (CREB) and modulator
  • inducible cAMP early repressor
  • hCREM 2alpha-b protein
  • hCREM 2beta-a protein
  • cAMP response element modulator
  • Synonym symbol(s) ICER, MGC41893, hCREM-2, MGC111110, MGC17881
    DNA
    TYPE functioning gene
    STRUCTURE 86.09 kb     8 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    alternative promoter
    cytosine-phosphate-guanine/HTF
    motif repetitive sequence   triplet
    text structure
  • CREM P2 promoter products known as ICER (inducible cAMP early repressor) induced in osteoblasts by parathyroid hormone
  • 15 CREM transcripts initiated from the P1 promoter, including 7 novel transcripts that result from alternative splicing, expressed by the osteoblasts
  • CREM promoter activity in T cells is controlled by CpG-DNA methylation
  • MAPPING cloned Y linked N status provisional
    Physical map
    LOC387650 10 hypothetical gene supported by BC000689; NM_021130; NR_000030 EPC1 10p11 enhancer of polycomb homolog 1, (Drosophila) FLJ32762 FLJ13031 ITGB1 10p11.2 integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) LOC340933 10p11.23 similar to 60S ribosomal protein L7a (Surfeit locus protein 3) (PLA-X polypeptide) NRP1 10p12 neuropilin 1 PARD3 10p11.23 par-3 partitioning defective 3 homolog (C. elegans) CUL2 10p11.2-p11.1 cullin 2 CREM 10p12.1-p11.1 cAMP responsive element modulator C10orf9 10p11.22 chromosome 10 open reading frame 9 CX40.1 10p11.22 connexin40.1 FZD8 10p11.22 frizzled homolog 8 (Drosophila) LOC389947 10 similar to ribosomal protein L7 LOC387651 10 similar to Pre-B cell enhancing factor precursor LOC389948 10 similar to MAP kinase-interacting serine/threonine kinase 1; MAP kinase interacting kinase 1 NY-BR-1 10p11.21 breast cancer antigen NY-BR-1 LOC387652 10 similar to hypothetical protein MGC33214 LOC219752 10p11.21 similar to TACC1 protein LOC387653 10 similar to tousled-like kinase 2; serine/threonine kinase; tousled-like kinase ZNF248 10p11.2 zinc finger protein 248 LOC387654 10 LOC387654 BA775A3.1 10p11 KRAB box zinc finger protein pseudogene LOC389949 10 similar to zinc finger protein 11b (KOX 2) ZNF25 10p11.2 zinc finger protein 25 (KOX 19) ZNF33A 10p11.2 zinc finger protein 33a (KOX 31)
    RNA
    TRANSCRIPTS type messenger
    text encodes a variety of different isoforms by utilizing four promoters and a complex pattern of alternative messenger ribonucleic acid (mRNA) splicing
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    8 initiation site 2225 - 300 - 2005 16059773
  • variant 1, isoform a or CREMT
  • activator tau2 isoform
  • P1 promoter
  • 8 exons
  • 4 initiation site 1991 - 120 - 2005 16059773
  • variant 4, isoform d or ICER1 and hCREM 2alpha-a
  • internal P2, specific 5'exon, five exons
  • 3 - 1955 - 108 - 2005 16059773
  • variant 7, isoform g or gamma and CREM 2alpha-b
  • lacking exon gamma
  • 4 - 1589 - 121 - 2005 16059773
  • variant 6, isoform f or CREM 2beta-a
  • lacking exon Ia
  • 3 - 1553 - 109 - 2005 16059773
  • variant 5, isoform e or gamma, CREM 2beta-b
  • lacking exon gamma and Ia
  • 4 - 1308 - 137 - 2005 16059773
  • variant 2, isoform b
  • 4 exons
  • 3 - 2065 - 112 - 2005 16059773
    variant 8, isoform h
    3 - 2108 - 95 - 2005 16059773
    variant 9, isoform i
    4 - 2144 - 102 - 2005 16059773
    variant 10, isoform J
    3 - 1663 - 113 - 2005 16059773
    variant 11, isoform k
    3 - 1706 - 96 - 2005 16059773
    variant 12, isoform 1
    6 - 2005 - 245 - 2005 16059773
    variant 13, isoform m or CREM theta2-tau2-beta
    5 - 1816 - 182 - 2005 16059773
  • variant 14, isoform n or CREM theta2-beta
  • major activator form in testes
  • 6 - 2160 - 270 - 2005 16059773
    variant 1, isoform o or CREM theta1-tau2-beta
    5 - 1971 - 207 - 2005 16059773
    variant 16, isoform p or CREM theta1-beta
    3 - 1786 - 96 - 2005 16059773
    variant 17, isoform q
    3 - 2188 - 95 - 2005 16059773
    variant 18, isoform r
    8 - 2687 - 248 in myometrium during pregnancy and labour 2005 16059773
    variant 19, isoform s or CREM type1 alpha
    6 - 2330 - 236 - 2005 16059773
    variant 20, isoform t
    7 - 2519 - 299 in myometrium during pregnancy and labour 2005 16059773
    variant 21, isoform u or activator tau2 alpha
    6 - 1938 - 221 - 2005 16059773
  • variant 22, isoform v
  • 5 exons
  • EXPRESSION
    Type widely
    constitutive of
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Endocrineadrenal gland   highly
     pancreas   highly
    Nervousbrainhindbrainmedulla oblongata  
    Reproductivemale systemtestis  highly
    Respiratoryrespiratory tractlarynx  highly
    Urinarykidney   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / Hematopoieticbone marrow   
    Connectivebone   
    Epithelialsecretoryglandularendocrine 
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Endocrineislet cell (alpha,beta...)
    Lymphoid/ImmuneT cell
    cell lineage lymphoid and non lymphoid
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a P box flanked by Gln(Q)-rich sequences lacking in ICER isoforms,
  • a bZIP domain
  • a KID (kinase-inducible) domain
  • conjugated PhosphoP
    mono polymer dimer
    HOMOLOGY
    interspecies homolog to murine Crem
    Homologene
    FAMILY
  • bZIP protein family
  • CATEGORY DNA associated , transcription factor , tumor suppressor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus,chromatin/chromosome
    basic FUNCTION
  • some isoforms (with a Gln-rich domain) function as activators and some (without the Gln-rich domains) as repressors of transcription
  • playing a key role within the hypothalamus-pituitary-gonadal axis, involved in spermiogenesis
  • cAMP inducible transcriptional repressor involved in the survival of neurons and in inhibition of neuronal suicide
  • involved in regulating gene expression in haploid spermatids
  • involved in the modulation of myometrial activity during pregnancy and parturition
  • role of CREB1 and CREM in stimulus-dependent transcription and neuronal homeostasis
  • potential part of an intracellular feedback mechanism limiting the activation of CRH transcription during stress
  • activator of gene transcription, competing, for the same DNA response element, with NR6A1 that suppresses gene transcription
  • component of the cAMP-mediated signal transduction during the spermatogenic cycle, playins a role in spermatid maturation
  • competes with CREB and AP1 for binding to the cathelicidin promoter and represses transcription and thus is involved in the innate hoste defense
  • plays an important role in regulating the neuroendocrine system and the circadian rythm
  • may be an important negative regulator of costimulation and APC-dependent T cell function
  • may be a tumor suppressor in leukemia
  • involvement of CREM in the lineage determination of effector memory CD4+ T cells, where it mediates epigenetic remodeling of the IL2 gene through the recruitment of DNMT3
  • potential role for CREM in chromatin remodeling of IL2 and IL17A and an enrichment of effector memory CD4+ T cells in SLE patients
  • CELLULAR PROCESS nucleotide, transcription
    PHYSIOLOGICAL PROCESS development , immunity/defense
    PATHWAY
    metabolism
    signaling signal transduction
    a component
  • CREM–FHL5 complex mediates the expression of many post-meiotic genes that are essential for normal spermatogenesis, thus providing a tissue-specific modulation mechanism for CREM transcription activity
  • INTERACTION
    DNA
  • binding to cAMP response element
  • binding DNA as a dimer
  • RNA
    small molecule
    protein
  • inhibiting calcineurin mediated IL2 expression (ICER)
  • interacting with CREBBP (CBP) after phosphorylation of Ser117 in the transactivation domain
  • binding to NR6A1 via its DNA binding domain
  • interacting with FHL5
  • CRH interacting with CREM (endogenous CREM formation is required for termination of CRH transcription)(
  • CREM mediates epigenetic remodeling of the IL2 and IL17A gene during T-cell differentiation in favor of effector memory T cells in health and disease
  • C-terminus (Yang 2009)
  • DAZAP1 regulates the splicing of CREM, CRISP2 and POT1 transcripts
  • cell & other
    REGULATION
    activated by mainly activated by its coactivator FHL5
    protein kinase A-mediated phosphorylation
    induced by cAMP
    Other regulated in a circadian manner in the pineal gland
    regulated by SFRS5 (regulates the splicing of CREM via its interactions with multiple exon splicing enhancers motifs present in the alternatively exons of CREM)
    stimulated by phosphorylation
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --low  
    down-regulated in the majority of chilhood leukemias
    constitutional     --over  
    in T cells from patients with systemic lupus erythematosus (SLE)
    Susceptibility panic disorder
    Variant & Polymorphism repeat shorter promoter P2 trinucleotide polymorphism (minor role)
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • in Crem-/- mice, modulated expression of cholesterogenic genes