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FLASH GENE

Symbol

CREM

contributors: mct - updated : 19-02-2018

HGNC name	cAMP responsive element modulator
HGNC id	2352

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_181571 8 initiation site 2225 NP_853549 - 300 - 2005 16059773 variant 1, isoform a or CREMT activator tau2 isoform P1 promoter 8 exons NM_182717 4 initiation site 1991 NP_874386 - 120 - 2005 16059773 variant 4, isoform d or ICER1 and hCREM 2alpha-a internal P2, specific 5'exon, five exons NM_182720 3 - 1955 NP_874389 - 108 - 2005 16059773 variant 7, isoform g or gamma and CREM 2alpha-b lacking exon gamma NM_182719 4 - 1589 NP_874388 - 121 - 2005 16059773 variant 6, isoform f or CREM 2beta-a lacking exon Ia NM_182718 3 - 1553 NP_874387 - 109 - 2005 16059773 variant 5, isoform e or gamma, CREM 2beta-b lacking exon gamma and Ia NM_001881 4 - 1308 NP_001872 - 137 - 2005 16059773 variant 2, isoform b 4 exons NM_182721 3 - 2065 NP_874390 - 112 - 2005 16059773 variant 8, isoform h NM_182722 3 - 2108 NP_874391 - 95 - 2005 16059773 variant 9, isoform i NM_182723 4 - 2144 NP_874392 - 102 - 2005 16059773 variant 10, isoform J NM_182724 3 - 1663 NP_874393 - 113 - 2005 16059773 variant 11, isoform k NM_182725 3 - 1706 NP_874394 - 96 - 2005 16059773 variant 12, isoform 1 NM_182769 6 - 2005 NP_877570 - 245 - 2005 16059773 variant 13, isoform m or CREM theta2-tau2-beta NM_182770 5 - 1816 NP_877571 - 182 - 2005 16059773 variant 14, isoform n or CREM theta2-beta major activator form in testes NM_182771 6 - 2160 NP_877572 - 270 - 2005 16059773 variant 1, isoform o or CREM theta1-tau2-beta NM_182772 5 - 1971 NP_877573 - 207 - 2005 16059773 variant 16, isoform p or CREM theta1-beta NM_182850 3 - 1786 NP_878270 - 96 - 2005 16059773 variant 17, isoform q NM_182853 3 - 2188 NP_878273 - 95 - 2005 16059773 variant 18, isoform r NM_183013 8 - 2687 NP_898831 - 248 in myometrium during pregnancy and labour 2005 16059773 variant 19, isoform s or CREM type1 alpha NM_183012 6 - 2330 NP_898830 - 236 - 2005 16059773 variant 20, isoform t NM_183011 7 - 2519 NP_898829 - 299 in myometrium during pregnancy and labour 2005 16059773 variant 21, isoform u or activator tau2 alpha NM_183060 6 - 1938 NP_898883 - 221 - 2005 16059773 variant 22, isoform v 5 exons

EXPRESSION

Type

widely

constitutive of

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Endocrine adrenal gland       highly   pancreas       highly Nervous brain hindbrain medulla oblongata     Reproductive male system testis     highly Respiratory respiratory tract larynx     highly Urinary kidney       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / Hematopoietic bone marrow       Connective bone       Epithelial secretory glandular endocrine

cells

System Cell Pubmed Species Stage Rna symbol Endocrine islet cell (alpha,beta...) Lymphoid/Immune T 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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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