CAMP responsive element modulator

CREM

Identifiers

CREM, CREM-2, ICER, hCREM-2, cAMP responsive element modulator

External IDs

MGI: 88495 HomoloGene: 84591 GeneCards: CREM

Gene ontology
Molecular function	• DNA binding • cAMP response element binding protein binding • transcription factor activity, sequence-specific DNA binding • protein binding • RNA polymerase II regulatory region sequence-specific DNA binding • transcriptional repressor activity, RNA polymerase II transcription regulatory region sequence-specific binding
Cellular component	• cytoplasm • transcription factor complex • nucleus
Biological process	• cell differentiation • regulation of transcription, DNA-templated • glycosphingolipid metabolic process • rhythmic process • transcription, DNA-templated • fatty acid metabolic process • multicellular organism development • retinoic acid receptor signaling pathway • regulation of circadian rhythm • spermatogenesis • glucose metabolic process • positive regulation of transcription from RNA polymerase II promoter • signal transduction • negative regulation of transcription from RNA polymerase II promoter
Sources:Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

Entrez


1390


12916

Ensembl


ENSG00000095794


ENSMUSG00000063889

UniProt


Q03060


P27699

RefSeq (mRNA)

NM_001267562 NM_001267563 NM_001267564 NM_001267565 NM_001267566
NM_001267567 NM_001267568 NM_001267569 NM_001267570 NM_001881 NM_181571 NM_182717 NM_182718 NM_182719 NM_182720 NM_182721 NM_182722 NM_182723 NM_182724 NM_182725 NM_182769 NM_182770 NM_182771 NM_182772 NM_182850 NM_182853 NM_183011 NM_183012 NM_183013 NM_183060 NM_001352445 NM_001352446 NM_001352465 NM_001352466 NM_001352467

NM_001110850 NM_001110851 NM_001110852 NM_001110853 NM_001110854
NM_001110855 NM_001110856 NM_001110857 NM_001110858 NM_001110859 NM_001271503 NM_001271504 NM_001271505 NM_001271506 NM_013498 NM_001311066 NM_001311067

RefSeq (protein)

NP_001254491 NP_001254492 NP_001254493 NP_001254494 NP_001254495
NP_001254496 NP_001254497 NP_001254498 NP_001254499 NP_001872 NP_853549 NP_874386 NP_874387 NP_874388 NP_874389 NP_874390 NP_874392 NP_874393 NP_877570 NP_877571 NP_877572 NP_877573 NP_898829 NP_898830 NP_898831 NP_898883 NP_001339374 NP_001339375 NP_001339394 NP_001339395 NP_001339396

NP_001104320 NP_001104321 NP_001104322 NP_001104323 NP_001104324
NP_001104325 NP_001104326 NP_001104327 NP_001104328 NP_001104329 NP_001258432 NP_001258433 NP_001258434 NP_001258435 NP_001297995 NP_001297996 NP_038526

Location (UCSC)

Chr 10: 35.13 – 35.21 Mb

Chr 18: 3.27 – 3.34 Mb

PubMed search

^[1]

^[2]

Wikidata

View/Edit Human

View/Edit Mouse

cAMP-responsive element modulator is a protein that in humans is encoded by the CREM gene,^[3]^[4]^[5] and it belongs to the CAMP-Responsive Element Binding protein family. It has multiple isoforms, which act either as repressors or activators.^[6] CREB family is important for in regulating transcription in response to various stresses, metabolic and developmental signals.^[7] CREM transcription factors also play an important role in many physiological systems, such as cardiac function,^[8] circadian rhythms,^[9] locomotion and spermatogenesis.^[10]

Function

This gene encodes a bZIP transcription factor that binds to the cAMP responsive element found in many viral and cellular promoters. It is an important component of cAMP-mediated signal transduction during the spermatogenetic cycle, as well as other complex processes. Alternative promoter and translation initiation site usage allows this gene to exert spatial and temporal specificity to cAMP responsiveness. Multiple alternatively spliced transcript variants encoding several different isoforms have been found for this gene, with some of them functioning as activators and some as repressors of transcriptnhunion.^[5]

Gene Location

The chromosomal location of CREM gene is 10p11.21, and it starts at 35415769 and ends at 35501886 bp from pter ( according to hg19-Feb_2009)^[11]

Interactions

CAMP responsive element modulator has been shown to interact with FHL5.^[12]^[13]

Disease relevance of CREM

Panic disorder

One study reported the DNA sequence variations in the gene for CREM in panic disorder patients. It showed a significant excess of the shorter eight-repeat allele and of genotypes containing the eight-repeat allele in panic disorder patients.^[14] The observed associations were limited to panic disorder without agoraphobia, and they were more prominent in females. But, the independent Italian and Spanish samples in this study did not support their results. Another family-based study showed little evidence of any susceptibility locus for panic disorder either within the CREM gene or in a nearby region on chromosome 10p11^[15]

spermiogenesis deficiency

Like Dr. Paolo Sassone-Corsi wrote in this article CREM is “a master-switch regulator in testis”.^[16] It plays an important role in the regulation of the expression of post-meiotic genes, and this has been supported by several studies using CREM-mutation mice.^[17] The results showed the first step in the process of sperm formation would be blocked if the germ cell development in mice CREM gene were disrupted. The cAMP response element sites can be found in the promoter region of some postmeiotic genes, so that the CREM can target and regulate these genes.^[16]

Two studies proved that treat the rats with Salvia hypoleuca and Alpina galanga can significantly increased the CREM gene expression.^[18]^[19]

systemic lupus erythematousus

Less IL-2 will be produced from T cells in humans or mice with systemic lupus erythematousus (SLE). Some studies showed that an increased level CREM was presented in the nucleus of T lymphocytes from SLE patients. The CREM bound to the -180 site of the IL-2 promoter to repress its transcription.^[20]

References

↑ "Human PubMed Reference:".
↑ "Mouse PubMed Reference:".
↑ Meyer TE, Habener JF (Nov 1992). "Cyclic AMP response element binding protein CREB and modulator protein CREM are products of distinct genes". Nucleic Acids Research. 20 (22): 6106. PMC 334485 . PMID 1461747. doi:10.1093/nar/20.22.6106.
↑ Masquilier D, Foulkes NS, Mattei MG, Sassone-Corsi P (Nov 1993). "Human CREM gene: evolutionary conservation, chromosomal localization, and inducibility of the transcript". Cell Growth & Differentiation. 4 (11): 931–7. PMID 7916662.
1 2 "Entrez Gene: CREM cAMP responsive element modulator".
↑ Foulkes, N. S.; Sassone-Corsi, P. (1992-02-07). "More is better: activators and repressors from the same gene". Cell. 68 (3): 411–414. ISSN 0092-8674. PMID 1739963. doi:10.1016/0092-8674(92)90178-f.
↑ Sassone-Corsi, P. (1995-01-01). "Transcription factors responsive to cAMP". Annual Review of Cell and Developmental Biology. 11: 355–377. ISSN 1081-0706. PMID 8689562. doi:10.1146/annurev.cb.11.110195.002035.
↑ Isoda, Takayoshi; Paolocci, Nazareno; Haghighi, Kobra; Wang, Congrong; Wang, Yibin; Georgakopoulos, Dimitrios; Servillo, Giuseppe; Della Fazia, Maria Agnese; Kranias, Evangelia G. (2003-02-01). "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. 17 (2): 144–151. ISSN 1530-6860. PMID 12554693. doi:10.1096/fj.01-0981com.
↑ Sassone-Corsi, P. (2000-06-01). "CREM: a master-switch regulating the balance between differentiation and apoptosis in male germ cells". Molecular Reproduction and Development. 56 (2 Suppl): 228–229. ISSN 1040-452X. PMID 10824972. doi:10.1002/(SICI)1098-2795(200006)56:2+<228::AID-MRD2>3.0.CO;2-B.
↑ Sassone-Corsi, P. (1998-08-01). "CREM: a master-switch governing male germ cells differentiation and apoptosis". Seminars in Cell & Developmental Biology. 9 (4): 475–482. ISSN 1084-9521. PMID 9813195. doi:10.1006/scdb.1998.0200.
↑ "CREM (cAMP responsive element modulator)". atlasgeneticsoncology.org. Retrieved 2016-10-16.
↑ Fimia GM, De Cesare D, Sassone-Corsi P (Nov 2000). "A family of LIM-only transcriptional coactivators: tissue-specific expression and selective activation of CREB and CREM". Molecular and Cellular Biology. 20 (22): 8613–22. PMC 102166 . PMID 11046156. doi:10.1128/MCB.20.22.8613-8622.2000.
↑ Fimia GM, De Cesare D, Sassone-Corsi P (Mar 1999). "CBP-independent activation of CREM and CREB by the LIM-only protein ACT". Nature. 398 (6723): 165–9. PMID 10086359. doi:10.1038/18237.
↑ Domschke, K.; Kuhlenbäumer, G.; Schirmacher, A.; Lorenzi, C.; Armengol, L.; DiBella, D.; Gratacos, M.; Garritsen, H. S.; Nöthen, M. M. (2003-02-01). "Human nuclear transcription factor gene CREM: genomic organization, mutation screening, and association analysis in panic disorder". American Journal of Medical Genetics Part B. 117B (1): 70–78. ISSN 1552-4841. PMID 12555239. doi:10.1002/ajmg.b.10018.
↑ Hamilton, Steven P.; Slager, Susan L.; Mayo, David; Heiman, Gary A.; Klein, Donald F.; Hodge, Susan E.; Fyer, Abby J.; Weissman, Myrna M.; Knowles, James A. (2004-04-01). "Investigation of polymorphisms in the CREM gene in panic disorder". American Journal of Medical Genetics Part B. 126B (1): 111–115. ISSN 1552-4841. PMID 15048659. doi:10.1002/ajmg.b.20121.
1 2 Krausz, Csilla; Sassone-Corsi, Paolo (2005-01-01). "Genetic control of spermiogenesis: insights from the CREM gene and implications for human infertility". Reproductive BioMedicine Online. 10 (1): 64–71. doi:10.1016/S1472-6483(10)60805-X.
↑ Nantel, F.; Monaco, L.; Foulkes, N. S.; Masquilier, D.; LeMeur, M.; Henriksén, K.; Dierich, A.; Parvinen, M.; Sassone-Corsi, P. (1996-03-14). "Spermiogenesis deficiency and germ-cell apoptosis in CREM-mutant mice". Nature. 380 (6570): 159–162. ISSN 0028-0836. PMID 8600390. doi:10.1038/380159a0.
↑ Jasem, Estakhr; Nasim, Javdan; Gholamreza, Motalleb; Naser, Sanchooli; Nader, Marzban; Maryam, Shams Lahijani; Abbas, Nikravesh; Vahid, Rostamian (2010-10-01). "Evaluation of the effects of Salvia hypoleuca on the cAMP-responsive element modulator (CREM) gene expression and spermatogenesis in rat". Middle East Fertility Society Journal. 15 (4): 274–277. doi:10.1016/j.mefs.2010.08.002.
↑ Mazaheri, Mahta; Shahdadi, Vahid; Nazari Boron, Ashraf (2016-10-16). "Molecullar and biochemical effect of alcohlic extract of Alpinia galanga on rat spermatogenesis process". Iranian Journal of Reproductive Medicine. 12 (11): 765–770. ISSN 1680-6433. PMC 4330656 . PMID 25709632.
↑ Juang, Yuang-Taung; Wang, Ying; Solomou, Elena E.; Li, Yansong; Mawrin, Christian; Tenbrock, Klaus; Kyttaris, Vasileios C.; Tsokos, George C. (2005-04-01). "Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV". Journal of Clinical Investigation. 115 (4): 996–1005. ISSN 0021-9738. PMC 1070410 . PMID 15841182. doi:10.1172/JCI22854.

External links

CREM protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
Human CREM genome location and CREM gene details page in the UCSC Genome Browser.

PDB gallery

1dh3: CRYSTAL STRUCTURE OF A CREB BZIP-CRE COMPLEX REVEALS THE BASIS FOR CREB FAIMLY SELECTIVE DIMERIZATION AND DNA BINDING

Transcription factors and intracellular receptors

(1) Basic domains

(1.1) Basic leucine zipper (bZIP)	Activating transcription factor AATF 1 2 3 4 5 6 7 AP-1 c-Fos FOSB FOSL1 FOSL2 JDP2 c-Jun JUNB JunD BACH 1 2 BATF BLZF1 C/EBP α β γ δ ε ζ CREB 1 3 L1 CREM DBP DDIT3 GABPA GCN4 HLF MAF B F G K NFE 2 L1 L2 L3 NFIL3 NRL NRF 1 2 3 XBP1
(1.2) Basic helix-loop-helix (bHLH)	ATOH1 AhR AHRR ARNT ASCL1 BHLH 2 3 9 ARNTL ARNTL ARNTL2 CLOCK EPAS1 FIGLA HAND 1 2 HES 5 6 HEY 1 2 L HES1 HIF 1A 3A ID 1 2 3 4 LYL1 MESP2 MXD4 MYCL1 MYCN Myogenic regulatory factors MyoD Myogenin MYF5 MYF6 Neurogenins 1 2 3 NeuroD 1 2 NPAS 1 2 3 OLIG 1 2 Pho4 Scleraxis SIM 1 2 TAL 1 2 Twist USF1
(1.3) bHLH-ZIP	AP-4 MAX MXD3 MITF MNT MLX MXI1 Myc SREBP 1 2
(1.4) NF-1	NFI A B C X SMAD R-SMAD 1 2 3 5 9 I-SMAD 6 7 4)
(1.5) RF-X	RFX 1 2 3 4 5 6 ANK
(1.6) Basic helix-span-helix (bHSH)	AP-2 α β γ δ ε

(2) Zinc finger DNA-binding domains

(2.1) Nuclear receptor (Cys₄)

subfamily 1	Thyroid hormone α β CAR FXR LXR α β PPAR α β/δ γ PXR RAR α β γ ROR α β γ Rev-ErbA α β VDR
subfamily 2	COUP-TF (I II Ear-2 HNF4 α γ PNR RXR α β γ Testicular receptor 2 4 TLX
subfamily 3	Steroid hormone Androgen Estrogen α β Glucocorticoid Mineralocorticoid Progesterone Estrogen related α β γ
subfamily 4	NUR NGFIB NOR1 NURR1
subfamily 5	LRH-1 SF1
subfamily 6	GCNF
subfamily 0	DAX1 SHP

(2.2) Other Cys₄

GATA
- 1
- 2
- 3
- 4
- 5
- 6
MTA
- 1
- 2
- 3
TRPS1

(2.3) Cys₂His₂

General transcription factors
- TFIIA
- TFIIB
- TFIID
- TFIIE
  - 1
  - 2
- TFIIF
- 1
- 2
  - TFIIH
  - 1
  - 2
  - 4
  - 2I
  - 3A
  - 3C1
  - 3C2

ATBF1
BCL
- 6
- 11A
- 11B
CTCF
E4F1
EGR
- 1
- 2
- 3
- 4
ERV3
GFI1
GLI-Krüppel family
- 1
- 2
- 3
- REST
- S1
- S2
- YY1
HIC
- 1
- 2
HIVEP
- 1
- 2
- 3
IKZF
- 1
- 2
- 3
ILF
- 2
- 3
KLF
- 1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 9
- 10
- 11
- 12
- 13
- 14
- 15
- 17
MTF1
MYT1
OSR1
PRDM9
SALL
- 1
- 2
- 3
- 4
SP
- 1
- 2
- 4
- 7
- 8
TSHZ3
WT1
Zbtb7
- 7A
- 7B
ZBTB
- 11
- 16
- 17
- 20
- 32
- 33
- 40
zinc finger
- 3
- 7
- 9
- 10
- 19
- 22
- 24
- 33B
- 34
- 35
- 41
- 43
- 44
- 51
- 74
- 143
- 146
- 148
- 165
- 202
- 217
- 219
- 238
- 239
- 259
- 267
- 268
- 281
- 295
- 300
- 318
- 330
- 346
- 350
- 365
- 366
- 384
- 423
- 451
- 452
- 471
- 593
- 638
- 644
- 649
- 655

(2.4) Cys₆

HIVEP1

(2.5) Alternating composition

AIRE
DIDO1
GRLF1
ING
- 1
- 2
- 4
JARID
- 1A
- 1B
- 1C
- 1D
- 2
JMJD1B

(2.6) WRKY

WRKY

(3) Helix-turn-helix domains

(3.1) Homeodomain	ARX CDX 1 2 CRX CUTL1 DBX 1 2 DLX 3 4 5 EMX 1 2 EN 1 2 FHL 1 2 3 HESX1 HHEX HLX Homeobox A1 A2 A3 A4 A5 A7 A9 A10 A11 A13 B1 B2 B3 B4 B5 B6 B7 B8 B9 B13 C4 C5 C6 C8 C9 C10 C11 C12 C13 D1 D3 D4 D8 D9 D10 D11 D12 D13 HOPX IRX 1 2 3 4 5 6 MKX LMX 1A 1B MEIS 1 2 MEOX2 MNX1 MSX 1 2 NANOG NKX 2-1 2-2 2-3 2-5 3-1 3-2 6-1 6-2 NOBOX PBX 1 2 3 PHF 1 3 6 8 10 16 17 20 21A PHOX 2A 2B PITX 1 2 3 POU domain PIT-1 BRN-3: A B C Octamer transcription factor: 1 2 3/4 6 7 11 OTX 1 2 PDX1 SATB2 SHOX2 SIX 1 2 3 4 5 VAX1 ZEB 1 2
(3.2) Paired box	PAX 1 2 3 4 5 6 7 8 9 PRRX 1 2 RAX
(3.3) Fork head / winged helix	E2F 1 2 3 4 5 FOX proteins A1 A2 A3 C1 C2 D3 D4 E1 E3 F1 G1 H1 I1 J1 J2 K1 K2 L2 M1 N1 N3 O1 O3 O4 P1 P2 P3 P4
(3.4) Heat shock factors	HSF 1 2 4
(3.5) Tryptophan clusters	ELF 2 4 5 EGF ELK 1 3 4 ERF ETS 1 2 ERG SPIB ETV 1 4 5 6 FLI1 Interferon regulatory factors 1 2 3 4 5 6 7 8 MYB MYBL2
(3.6) TEA domain	transcriptional enhancer factor 1 2 3 4

(4) β-Scaffold factors with minor groove contacts

(4.1) Rel homology region	NF-κB NFKB1 NFKB2 REL RELA RELB NFAT C1 C2 C3 C4 5
(4.2) STAT	STAT 1 2 3 4 5 6
(4.3) p53	p53 TBX 1 2 3 5 19 21 22 TBR1 TBR2 TFT MYRF TP63
(4.4) MADS box	Mef2 A B C D SRF
(4.6) TATA-binding proteins	TBP TBPL1
(4.7) High-mobility group	BBX HMGB 1 2 3 4 HMGN 1 2 3 4 HNF 1A 1B LEF1 SOX 1 2 3 4 5 6 8 9 10 11 12 13 14 15 18 21 SRY SSRP1 TCF 3 4 TOX 1 2 3 4
(4.9) Grainyhead	TFCP2
(4.10) Cold-shock domain	CSDA YBX1
(4.11) Runt	CBF CBFA2T2 CBFA2T3 RUNX1 RUNX2 RUNX3 RUNX1T1

(0) Other transcription factors

(0.2) HMGI(Y)	HMGA 1 2 HBP1
(0.3) Pocket domain	Rb RBL1 RBL2
(0.5) AP-2/EREBP-related factors	Apetala 2 EREBP B3
(0.6) Miscellaneous	ARID 1A 1B 2 3A 3B 4A CAP IFI 16 35 MLL 2 3 T1 MNDA NFY A B C Rho/Sigma

see also transcription factor/coregulator deficiencies

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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