Many hormones that stimulate intracellular signaling pathways utilizing the second messenger cAMP affect gene expression in target
cells through the activation of cAMP-responsive transcriptional regulatory proteins. Two of the best characterized of these are the
cAMP-response element (CRE)-binding protein (CREB) and the CRE-modulatory protein (CREM). CREB and CREM are
expressed as a family of proteins that have diverse activities in either stimulating or repressing gene transcription.
From a mouse pituitary cDNA library, Foulkes et al. (1991) isolated a protein highly homologous to nuclear factor CREB, an activator of
cAMP-responsive promoter elements (CREs). Unlike CREB, which is expressed uniformly in several cell types, the CREM gene showed cell-specific expression.
Downstream of the stop codon was a second out-of-frame DNA-binding domain. They identified 3 mRNA isoforms that appeared to be formed
through differential cell-specific splicing. In contrast to CREB, CREM acts as a down-regulator of cAMP-induced transcription.
NCBI Summary:
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 transcription.
General function
Nucleic acid binding, DNA binding, Transcription factor
Comment
Mukherjee A et al examined the expression and regulation of the CREM gene in the rat ovary and in granulosa cells, to determine whether repressor isoforms of CREM might have a role in the LH-mediated suppression of inhibin alpha-subunit gene expression that occurs just before
ovulation. The predominant CREM mRNAs in the ovary correspond to previously described internal transcripts of the
CREM gene that encode the inducible cAMP early repressor (ICER).
Cellular localization
Nuclear
Comment
Ovarian function
Follicle development, Antral follicle growth
Comment
Mukherjee A et al reported that ICER mRNAs are strongly induced in the ovary by exogenous
gonadotropins in immature rats and are transiently expressed in the ovary immediately after the preovulatory LH surge in adult cycling
rats. Although ICER is expressed in multiple ovarian cell types, expression in granulosa cells is observed only in response to LH
stimulation. ICER mRNAs are also induced by the activation of cAMP-signaling pathways in cultured primary granulosa cells.
To determine whether ICER can act as a functional repressor to modulate potential target genes such as the inhibin alpha-subunit gene, an
ICER expression construct was transiently co-transfected into a granulosa cell line along with an inhibin alpha-subunit
promoter-luciferase reporter gene Mukherjee A et al . Both basal and cAMP-induced expression of the inhibin alpha-subunit promoter were suppressed
by ICER.
These findings are consistent with a role for repressors such as ICER in mediating the suppression of
inhibin alpha-subunit gene expression that occurs in the ovary at the time of the preovulatory LH surge.
Expression regulated by
FSH
Comment
Kameda T et al identified rat ovarian genes that were rapidly induced by FSH in the cultured rat granulosa cells by means of subtraction cloning.
Complementary DNA clones encoding cAMP responsive element binding modulator (CREM) were identified as one of the FSH
inducible genes. Northern blotting and reverse transcription and polymerase chain reaction (RT-PCR) analyses revealed that only the
repressor type of CREM gene products, ICER (inducible cAMP early repressor) isoforms, were induced by FSH treatment in
cultured rat granulosa cells. The induction of ICER by FSH was mimicked by reagents known to increase intracellular cAMP levels,
indicating that the induction is through cAMP and protein kinase A signal transduction system. Induction of ICER was also confirmed
as the protein levels. Electrophoretic mobility shift assay of granulosa cell extracts with a radiolabeled double stranded oligonucleotide
corresponding to somatostatin cAMP responsive element also revealed that only the ICER proteins were induced by FSH treatment,
whereas levels of CREM proteins were nearly constant regardless of the FSH treatment. It was suggested that FSH-induced and cAMP-mediated induction and attenuation of transcriptional responses by CREM gene products may be a key
mechanistic component for the granulosa cell differentiation and proliferation.
Ovarian localization
Granulosa
Comment
Mechanism of Repression of the Inhibin {alpha} Subunit Gene by Inducible cAMP: Early Repressor Burkart AD, et al .
The rodent ovary is regulated throughout the reproductive cycle to maintain normal cyclicity. Ovarian follicular development is controlled by changes in gene expression in response to the gonadotropins FSH (FSH) and LH (LH). The inhibin alpha subunit gene belongs to a group of genes that is positively regulated by FSH and negatively regulated by LH. Previous studies established an important role for inducible cAMP early repressor (ICER) in repression of alpha-inhibin. These current studies investigate the mechanisms of repression by ICER. It is not clear if all four ICER isoforms expressed in the ovary can act as repressors of the inhibin alpha subunit gene. Electrophoretic mobility shift assays (EMSAs) demonstrate binding of all isoforms to the inhibin alpha subunit CRE, and transfection studies demonstrate that all isoforms can repress the inhibin alpha subunit gene. Repression by ICER is dependent on its binding to DNA as demonstrated by mutations to ICER's DNA binding domain. These mutational studies also demonstrate that repression by ICER is not dependent on heterodimerization with CREB. Competitive EMSAs show that ICER effectively competes with CREB for binding to the inhibin alpha CRE in vitro. Chromatin immunoprecipitation (ChIP) assays demonstrate a replacement of CREB dimers bound to the inhibin alpha CRE by ICER dimers in ovarian granulosa cells in response to LH signaling. Thus, there is a temporal association of transcription factors bound to the inhibin alpha-CRE controlling inhibin alpha subunit gene expression.
Follicle stages
Antral, Preovulatory
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: fertile Comment: The specific role of CREM
in spermiogenesis was addressed by Nantel et al. (1996) using CREM-deficient mice generated by homologous recombination. Analysis of the seminiferous
epithelium in mutant male mice revealed postmeiotic arrest at the first step of spermiogenesis. Late spermatids were completely absent, and there was a significant
increase in apoptotic germ cells. They showed that CREM deficiency results in the lack of postmeiotic cell-specific gene expression.