SpermatogenesisOnline 1.0
 

Tag Content
SG ID
SG00000445 
UniProt Accession
Theoretical PI
6.35  
Molecular Weight
38940 Da  
Genbank Nucleotide ID
Genbank Protein ID
Gene Name
CREM 
Gene Synonyms/Alias
 
Protein Name
cAMP-responsive element modulator 
Protein Synonyms/Alias
Inducible cAMP early repressor;ICER 
Organism
Homo sapiens (Human) 
NCBI Taxonomy ID
9606 
Chromosome Location
chr:10;35415719-35501886;1
View in Ensembl genome browser  
Function in Stage
Function in Cell Type
Description
Several CREM repressor transcripts are present in adult human testes, and altered transcript splicing is associated with impaired spermatogenesis. CREM plays a role also in human spermatogenesis and that the absence of "the CREM switch" can be associated to spermatogenic arrest. 
The information of related literatures
1. R. Behr and G. F. Weinbauer (2000) CREM activator and repressor isoforms in human testis. Mol Hum Reprod 6(11): 967-72. 

Abstract
cAMP responsive element modulator (CREM) activators are specifically expressed in haploid germ cells prior to cell elongation and are essential for spermatid development in mice. Recent studies indicate that CREM activators are also involved in the process of spermatid maturation in men. Unlike the activators, CREM repressors were suggested to be absent from adult mouse and dog testes. The present work investigates CREM transcripts in human testis with normal (n = 4) and impaired spermatogenesis (n = 2). Two activator transcripts could be identified corresponding to the tau2 isoform with and without exon gamma. Interestingly, four CREM repressors could be isolated from specimens with complete spermatogenesis. These were gamma-repressor (exons B, E, F, H, I(b)), CREM DeltaC-F, beta (exons B, G, H, I(b)), CREM DeltaC-G, beta (exons B, H, I(b)), and CREM DeltaC-G, alpha (exons B, H, I(a), I(b)). These isoforms were also present in cynomolgus monkey testes. A novel CREM splice variant (CREM DeltaC-H) was detected in a specimen with spermatid maturation defect. Beyond that, inaccurate CREM splicing, giving rise to inactive transcripts, was encountered in a specimen with impaired spermatogenesis. In conclusion, several CREM repressor transcripts are present in adult human testes, and altered transcript splicing is associated with impaired spermatogenesis. PMID: [11044457] 

2. A. Peri and M. Serio (2000) The CREM system in human spermatogenesis. J Endocrinol Invest 23(9): 578-83. 

Abstract
Spermatogenesis is a multi-step process, regulated by endocrine, paracrine and autocrine signals, through which immature germ cells differentiate into spermatozoa. The cAMP-dependent transcription factor CREM directs in the testis the expression of genes related to the structuring of mature spermatozoa. CREM gene expression originates different isoforms, which in turn can be divided into activators or repressors of gene expression. Whereas only CREM repressors are expressed in pre-meiotic germ cells in mice, a switch to the expression of the CREM activator tau occurs in post-meiotic germ cells. In addition, mice lacking CREM gene are infertile and present an arrest of germ cell maturation at the stage of round spermatid. We have demonstrated that CREM gene is expressed also in human germ cells and that a switch from the expression of repressors to activators is present in normospermic men. In particular, CREM tau mRNA is located in the cytoplasm of round spermatids. Conversely, in patients showing a testicular pattern of round spermatid maturation arrest only CREM repressors are expressed. Other reports have confirmed our data, supporting the hypothesis that CREM plays a role also in human spermatogenesis and that the absence of "the CREM switch" can be associated to spermatogenic arrest. PMID: [11079452] 

3. I. Palermo, G. Arcidiacono, N. Barone, F. Italia, M. Arizzi, G. Spera, G. Bartoloni, S. Di Mercurio, E. Vicari and A. E. Calogero (2004) Normal expression of isoforms activating cyclic adenosine monophosphate responsive element modulator in patients with spermatid maturation arrest. Fertil Steril 82 Suppl 3(): 1072-6. 

Abstract
OBJECTIVE PMID: [15474076] 

4. D. Fiszer, M. Bialas, N. Rozwadowska, W. Kosicki, P. Jedrzejczak and M. Kurpisz (2007) Crem activator isoforms in normal and impaired human spermatogenesis analyzed by real time RT-PCR. Arch Androl 53(5): 257-65. 

Abstract
cAMP responsive element modulator (CREM) activator isoforms are involved in mammalian spermatogenesis and spermiogenesis. CREM proteins are highly expressed in postmeiotic germ cells of rodents and primates. Homozygous CREM inactivated mice exhibit round spermatid maturation arrest. The lack of CREM expression at both the mRNA and protein levels is associated with spermatid maturation arrest in infertile patients. Using real-time RT-PCR, we have examined the levels of CREM activator isoform mRNAs PMID: [18309898] 

5. G. F. Weinbauer, R. Behr, M. Bergmann and E. Nieschlag (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. Mol Hum Reprod 4(1): 9-15. 

Abstract
Mice lacking the functional cAMP responsive element modulator (CREM) gene, a component of cAMP-mediated signal transduction, exhibit a specific arrest of round spermatid development although follicle stimulating hormone (FSH) and androgen secretion are not impaired. We studied testicular expression of CREM protein by immunocytochemistry in four patients with complete spermatogenesis (obstructive azoospermia), in 20 infertile patients with round spermatid maturation arrest (n = 10) or mixed atrophy (n = 10) and in six prostate cancer patients undergoing orchidectomy. Concentrations of testosterone were below normal in three patients. Concentrations of luteinizing hormone (LH) were lowered in two patients and elevated in one patient. FSH concentrations were above normal in ten patients. During normal spermatogenesis, CREM was expressed in nuclei of round spermatids in stages I-III of spermatogenesis but not in elongating spermatids. Western blot analysis of testes from prostate cancer patients indicated a major CREM band of approximately 35 kDa. Among patients with predominant round spermatid maturation arrest, CREM expression was significantly reduced (P < 0.05) or undetectable as revealed by quantitative image analysis. CREM-negative spermatids failed to progress beyond stage III of spermatogenesis. Our observations suggest a role for CREM in human spermatid development and raise the possibility that altered CREM expression could be associated with spermatid maturation defects in some cases of idiopathic male infertility. PMID: [9510006] 

Back to Top
Figures for illustrating the function of this protein/gene
Ref: G. F. Weinbauer, R. Behr, M. Bergmann and E. Nieschlag (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. Mol Hum Reprod 4(1): 9-15. PMID: [9510006]
Ref: G. F. Weinbauer, R. Behr, M. Bergmann and E. Nieschlag (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. Mol Hum Reprod 4(1): 9-15. PMID: [9510006]
Function
Transcriptional regulator that binds the cAMP responseelement (CRE), a sequence present in many viral and cellularpromoters. Isoforms are either transcriptional activators orrepressors. Plays a role in spermatogenesis and is involved inspermatid maturation (By similarity). 
Back to Top
Subcellular Location
Nucleus. 
Tissue Specificity
Expressed in testes (round spermatids) (atprotein level). Isoform 14 is the major activator form in testes. 
Gene Ontology
GO IDGO termEvidence
GO:0005634 C:nucleus NAS:UniProtKB.
GO:0005667 C:transcription factor complex IEA:Compara.
GO:0008140 F:cAMP response element binding protein binding NAS:UniProtKB.
GO:0003677 F:DNA binding NAS:UniProtKB.
GO:0043565 F:sequence-specific DNA binding IEA:InterPro.
GO:0003700 F:sequence-specific DNA binding transcription factor activity IEA:InterPro.
GO:0030154 P:cell differentiation IEA:UniProtKB-KW.
GO:0006631 P:fatty acid metabolic process IEA:Compara.
GO:0006006 P:glucose metabolic process IEA:Compara.
GO:0006687 P:glycosphingolipid metabolic process IEA:Compara.
GO:0007275 P:multicellular organismal development IEA:UniProtKB-KW.
GO:0042752 P:regulation of circadian rhythm IEA:Compara.
GO:0006355 P:regulation of transcription, DNA-dependent IDA:UniProtKB.
GO:0048384 P:retinoic acid receptor signaling pathway IEA:Compara.
GO:0007165 P:signal transduction TAS:ProtInc.
GO:0007283 P:spermatogenesis IEA:UniProtKB-KW.
GO:0006351 P:transcription, DNA-dependent IEA:UniProtKB-KW.
Back to Top
Interpro
IPR004827;    bZIP.
IPR011616;    bZIP_1.
IPR003102;    Coactivator_CBP_pKID.
IPR001630;    Leuzip_CREB.
Back to Top
Pfam
PF00170;    bZIP_1;    1.
PF02173;    pKID;    1.
Back to Top
SMART
SM00338;    BRLZ;    1.
Back to Top
PROSITE
PS50217;    BZIP;    1.
PS00036;    BZIP_BASIC;    1.
PS50953;    KID;    1.
Back to Top
PRINTS
PR00041;    LEUZIPPRCREB.;   
Back to Top
Created Date
18-Oct-2012 
Record Type
Experiment identified 
Protein sequence Annotation
CHAIN         1    361       cAMP-responsive element modulator.
                             /FTId=PRO_0000076607.
DOMAIN      104    163       KID.
DOMAIN      302    361       bZIP.
REGION      303    328       Basic motif (By similarity).
REGION      330    351       Leucine-zipper (By similarity).
MOD_RES     136    136       Phosphoserine (By similarity).
MOD_RES     145    145       Phosphoserine (By similarity).
MOD_RES     287    287       Phosphoserine.
MOD_RES     290    290       Phosphoserine.
MOD_RES     293    293       Phosphoserine.
VAR_SEQ       1    240       Missing (in isoform 6, isoform 7, isoform
                             8 and isoform 9).
                             /FTId=VSP_026075.
VAR_SEQ       1    104       Missing (in isoform 5, isoform 10,
                             isoform 11, isoform 12, isoform 19 and
                             isoform 20).
                             /FTId=VSP_025035.
VAR_SEQ       1     16       Missing (in isoform 22).
                             /FTId=VSP_043782.
VAR_SEQ       1     12       MSKCARKKYIKT -> MNRTQELSGQLS (in isoform
                             21).
                             /FTId=VSP_043713.
VAR_SEQ      13    260       Missing (in isoform 21).
                             /FTId=VSP_043714.
VAR_SEQ      58    106       Missing (in isoform 4, isoform 13,
                             isoform 14, isoform 15, isoform 16 and
                             isoform 22).
                             /FTId=VSP_000599.
VAR_SEQ     105    258       Missing (in isoform 20).
                             /FTId=VSP_043580.
VAR_SEQ     105    105       Q -> MWWHQHNLCFRRPIEEDYSSGDVEEK (in
                             isoform 10, isoform 11 and isoform 19).
                             /FTId=VSP_026076.
VAR_SEQ     105    105       Q -> M (in isoform 5 and isoform 12).
                             /FTId=VSP_025036.
VAR_SEQ     107    185       Missing (in isoform 15 and isoform 16).
                             /FTId=VSP_026077.
VAR_SEQ     186    248       Missing (in isoform 4, isoform 11,
                             isoform 12, isoform 16, isoform 17 and
                             isoform 18).
                             /FTId=VSP_000600.
VAR_SEQ     186    202       IAIAQGGTIQISNPGSD -> SMYAAIRYDTVLALSLL
                             (in isoform 22).
                             /FTId=VSP_043783.
VAR_SEQ     203    361       Missing (in isoform 22).
                             /FTId=VSP_043784.
VAR_SEQ     241    248       PGSQVVVQ -> MAVTGDDT (in isoform 6,
                             isoform 7, isoform 8 and isoform 9).
                             /FTId=VSP_026078.
VAR_SEQ     249    260       Missing (in isoform 2, isoform 3, isoform
                             4, isoform 5, isoform 7, isoform 9,
                             isoform 10, isoform 14, isoform 15,
                             isoform 17 and isoform 18).
                             /FTId=VSP_025037.
VAR_SEQ     261    261       A -> T (in isoform 4, isoform 11 and
                             isoform 12).
                             /FTId=VSP_000601.
VAR_SEQ     317    361       KECRRRKKEYVKCLESRVAVLEVQNKKLIEELETLKDICSP
                             KTDY -> RECRRKKKEYVKCLENRVAVLENQNKTLIEELK
                             ALKDLYCHKVE (in isoform 3, isoform 6,
                             isoform 7, isoform 18, isoform 20 and
                             isoform 21).
                             /FTId=VSP_025038.
VARIANT     270    270       Q -> R (in dbSNP:rs1804604).
                             /FTId=VAR_055561.
CONFLICT     49     49       N -> I (in Ref. 11; AAC60616/AAC60617).
CONFLICT     55     55       A -> R (in Ref. 10; CAA78858).
CONFLICT     57     61       VSVAG -> CSELR (in Ref. 11; AAC60616/
                             AAC60617).
CONFLICT    292    292       H -> R (in Ref. 3; BAA03564/BAA03565/
                             BAA03566/BAA03567).
Back to Top
Nucleotide Sequence
Length: 1199 bp   Go to nucleotide: FASTA
Protein Sequence
Length: 361 bp   Go to amino acid: FASTA
The verified Protein-Protein interaction information
UniProt
 Gene Symbol Ref Databases
CAMK2DHPRD 
ATF1HPRD 
PRKCAHPRD 
CD34BioGRID 
CDK1HPRD 
CREB3L4BioGRID 
_BioGRID 
CREBBPHPRD 
CREB3L1HPRD 
CREB1HPRD 
CREMHPRD 
CREMHPRD 
FHL5BioGRID 
HDAC1BioGRID 
SPENString 
TBPBioGRID 
CREBBPHPRD 
CREB1HPRD 
HDAC1BioGRID 
TAF4BioGRID 
TBPBioGRID 
CDC34HPRD 
KCNIP3HPRD 
CSNK2A1HPRD 
CSNK2A2HPRD 
FHL5BioGRID 
GSK3AHPRD 
GSK3BHPRD 
HDAC1BioGRID 
PRKACAHPRD 
CSNK1A1HPRD 
CAMK2DHPRD 
PRKCAHPRD 
SPENString 
_HPRD 
TBPHPRD 
KCNIP3HPRD 
HDAC1BioGRID 
CSNK1A1HPRD 
PRKCAHPRD 
SPI1HPRD 
TAF4HPRD 
TBPHPRD 
Other Protein-Protein interaction resources
String database  
View Microarray data
Temporarily unavailable 
Comments