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Results for “Cyclic AMP Response Element Modulator”

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PubMed2004

Testis-specific transcription mechanisms promoting male germ-cell differentiation.

Male germ-cell differentiation requires spermatogenic stage- and cell-specific gene expression that is achieved by unique chromatin remodeling, transcriptional control and the expression of testis-specific genes or isoforms. Recent findings have shown that the testis has specialized transcription complexes that coordinate the differentiation program of spermatogenesis. There are male germ cell-specific differences in the components of the general transcription machinery. These include upregulated expression of the TATA-binding protein (TBP) family and its associated cofactors. Importantly, a member of the TBP family, TBP-like factor (TLF), has a distribution pattern that is dependent on the spermatogenic cycle and is essential for spermatogenesis. Interestingly TBP-associated factor (TAF7), a factor of the transcription factor (TF)IID complex, is exchanged at a critical stage in germ cell development for the testis-specific paralogue TAF7L. A compelling amount of data has established that cAMP-response-element modulator (CREM), a transcription factor responsive to the cAMP signal transduction pathway, drives expression of key testis-specific genes. In this review we summarize recent advances in the transcription machinery that is testis-specific, gene-selective and necessary for the process of spermatogenesis.

Animals↗

PubMed1996

Genetic characterization of transactivation of the human T-cell leukemia virus type 1 promoter: Binding of Tax to Tax-responsive element 1 is mediated by the cyclic AMP-responsive members of the CREB/ATF family of transcription factors.

To achieve a better understanding of the mechanism of transactivation by Tax of human T-cell leukemia virus type 1 Tax-responsive element 1 (TRE-1), we developed a genetic approach with Saccharomyces cerevisiae. We constructed a yeast reporter strain containing the lacZ gene under the control of the CYC1 promoter associated with three copies of TRE-1. Expression of either the cyclic AMP response element-binding protein (CREB) or CREB fused to the GAL4 activation domain (GAD) in this strain did not modify the expression of the reporter gene. Tax alone was also inactive. However, expression of the reporter gene was induced by coexpression of Tax and CREB. This effect was stronger with the GAD-CREB fusion protein. Analysis of different CREB mutants with this genetic system indicated that the C-terminal 92 amino acid residues, which include the basic domain and the leucine zipper, are necessary and sufficient to mediate transactivation by Tax. To identify cellular proteins binding to TRE-1 in a Tax-dependent manner, this strain was also used to screen a library of human cDNAs fused to GAD. Of five positive clones isolated from 0.75 x 10(6) yeast colonies, four were members of the CREB/activating transcription factor (ATF) family: CREB, two isoforms of the cyclic AMP-responsive element modulator (CREM), and ATF-1. Interestingly, these three proteins can be phosphorylated by protein kinase A and thus form a particular subgroup within the CREB/ATF family. Expression of ATF-2 in S. cerevisiae did not activate TRE-1 in the presence of Tax. This shows that in a eukaryotic nucleus, Tax specifically interacts with the basic domain-leucine zipper region of ATF-1, CREB, and CREM. The fifth clone identified in this screening corresponded to the Ku autoantigen p70 subunit. When fused to GAD, the C-terminal region of Ku was able to activate transcription via TRE-1 but this activation was not dependent on Tax.

Activating Transcription Factors↗

PubMed1995

Thyroid-stimulating hormone (TSH)-directed induction of the CREM gene in the thyroid gland participates in the long-term desensitization of the TSH receptor.

Thyroid gland function is regulated by the hypothalamic-pituitary axis via the secretion of TSH, according to environmental, developmental, and circadian stimuli. TSH modulates both the secretion of thyroid hormone and gland trophism through interaction with a specific guanine nucleotide-binding protein-coupled receptor (TSH receptor; TSH-R), which elicits the activation of the cAMP-dependent signaling pathway. After TSH stimulation, the levels of TSH-R RNA are known to decrease dramatically within a few hours. This phenomenon ultimately leads to homologous long-term desensitization of the TSH-R. Here we show that TSH drives the induction of the inducible cAMP early repressor (ICER) isoform of the cAMP response element (CRE) modulator gene both in rat thyroid gland and in the differentiated thyroid cell line FRTL-5. The kinetics of ICER protein induction mirrors the down-regulation of TSH-R mRNA. ICER binds to a CRE-like sequence in the TSH-R promoter and represses its expression. Thus, ICER induction by TSH in the thyroid gland represents a paradigm of the molecular mechanism by which pituitary hormones elicit homologous long-term desensitization.

Animals↗

PubMed2000

Suppression of T cell function: a potential role for transcriptional repressor ICER.

In this article, we review the inducible cAMP early repressor (ICER) and its possible critical involvement in modulation of T cell responsiveness by its capacity to transcriptionally attenuate interleukin-2 (IL-2) gene expression. It seems clear that the failure to produce the IL-2 is an important determinant of anergy induction. It is important that the CD28-responsive element (CD28RE), a composite DNA binding element consisting of NFAT and cyclic AMP-responsive (CRE)-like motifs in position of -160 of IL-2 promoter has the high affinity for ICER binding as well as NFAT/ICER complex formation. Moreover, CD28RE with adjacent DNA sequences was also shown to be essential for conferring anergy in T lymphocytes. Because ICER does not possess a transactivation domain required for the recruitment of CBP/p300, the binding of ICER to CD28RE and/or composite motifs containing CRE-like DNA motifs may lead to uncoupling of CBP/p300 thus extinguishing IL-2 expression as well as expression of numerous other cytokines and chemokines.

Cell Division↗

PubMed2002

Gene expression analysis of spontaneously hypertensive rat cerebral cortex following transient focal cerebral ischemia.

Identification of novel modulators of ischemic neuronal death helps in developing new strategies to prevent the stroke-induced neurological dysfunction. Hence, the present study evaluated the gene expression changes in rat cerebral cortex at 6 and 24 h of reperfusion following transient middle cerebral artery occlusion (MCAO) by GeneChip analysis. Transient MCAO resulted in selective increased mRNA levels of genes involved in stress, inflammation, transcription and plasticity, and decreased mRNA levels of genes which control neurotransmitter function and ionic balance. In addition to a number of established ischemia-related genes, many genes not previously implicated in transient focal ischemia-induced brain damage [suppressor of cytokine signaling (SOCS)-3, cAMP responsive element modulator (CREM), cytosolic retinol binding protein (CRBP), silencer factor-B, survival motor neuron (SMN), interferon-gamma regulatory factor-1 (IRF-1), galanin, neurotrimin, proteasome subunit RC8, synaptosomal-associated protein (SNAP)-25 A and B, synapsin 1a, neurexin 1-beta, ras-related rab3, vesicular GABA transporter (VGAT), digoxin carrier protein, neuronal calcium sensor-1 and neurodap] were observed to be altered in the ischemic cortex. Real-time PCR confirmed the GeneChip results for several of these transcripts. SOCS-3 is a gene up-regulated after ischemia which modulates inflammation by controlling cytokine levels. Antisense knockdown of ischemia-induced SOCS-3 protein expression exacerbated transient MCAO-induced infarct volume assigning a neuroprotective role to SOCS-3, a gene not heretofore implicated in ischemic neuronal damage.

Animals↗

PubMed1997

Rhythmic transcription: the molecular basis of circadian melatonin synthesis.

Adaptation to a changing environment is an essential feature of physiological regulation. The day/night rhythm is translated into hormonal oscillations governing the physiology of all living organisms. In mammals the pineal gland is responsible for the synthesis of the hormone melatonin in response to signals originating from the endogenous clock located in the hypothalamic suprachiasmatic nucleus (SCN). The molecular mechanisms involved in rhythmic synthesis of melatonin involve the CREM gene, which encodes transcription factors responsive to activation of the cAMP signalling pathway. The CREM product, ICER, is rhythmically expressed and participates in a transcriptional autoregulatory loop which also controls the amplitude of oscillations of serotonin N-acetyl transferase (AANAT), the rate-limiting enzyme of melatonin synthesis. In contrast, chick pinealocytes possess an endogenous circadian pacemaker which directs AANAT rhythmic expression. cAMP-responsive activator transcription factors CREB and ATF1 and the repressor ICER are highly conserved in the chick with the notable exception of ATF1 that possesses two glutamine-rich domains in contrast to the single domain encountered to date in mammalian systems. ICER is cAMP inducible and undergoes a characteristic day-night oscillation in expression reminiscent of AA-NAT, but with a peak towards the end of the night. Interestingly CREB appears to be phosphorylated constitutively with a transient fall occurring at the beginning of the night. Thus, a transcription factor modulates the oscillatory levels of a hormone.

Acetylserotonin O-Methyltransferase↗

PubMed2006

Induction of inducible cAMP early repressor expression in nucleus accumbens by stress or amphetamine increases behavioral responses to emotional stimuli.

Previous research has shown that cAMP response element (CRE)-mediated transcription is activated in the nucleus accumbens, a major brain reward region, by a variety of environmental stimuli and contributes to neuroadaptations to these stimuli. CRE-binding protein (CREB) is the most studied activator of CRE transcription and has been implicated in this brain region as a gating mechanism for behavioral responses to emotional stimuli. Little attention, however, has been given to naturally occurring inhibitors of CRE-mediated transcription, such as the inducible cAMP early repressor (ICER), an inhibitory product of the CRE modulator gene. In the present study, we investigated the extent to which ICER is induced in the nucleus accumbens by two types of environmental stimuli, stress and amphetamine, and characterized how induction of ICER in this region affects complex behavior. We show that stress and amphetamine each induces ICER expression and that overexpression of ICER in the nucleus accumbens, using viral-mediated gene transfer, increases behavioral responses to both rewarding and aversive emotional stimuli. For example, ICER overexpression increases sensitivity to amphetamine-stimulated locomotor activity as well as to natural rewards such as sucrose and social grooming. However, ICER overexpression also increases measures of anxiety in the elevated plus maze and neophobia to novel tastes. Finally, ICER produces an antidepressant-like effect in the forced swim test, further indication of an enhanced active response to stress. These results suggest that ICER is an important mechanism for modulating CRE-mediated transcription in the nucleus accumbens.

Amphetamine↗

PubMedDate not supplied

Spinal cord contusion impairs sperm motility in the rat without disrupting spermatogenesis.

Our previous studies demonstrated various abnormalities in spermatogenesis after spinal cord injury (SCI) in cord-transected rats. In this study, we examined whether abnormalities in spermatogenesis in SCI rats were related to the degree of SCI. We used spinal cord-contused (SCC) rats as a model. Adult male Sprague-Dawley rats were subjected to various degrees of cord contusion caused by the weight of a rod dropped from different heights (12.5, 25, 50, and 75 mm) using a New York University IMPACTOR. Testicular histology revealed persistent complete spermatogenesis in all SCC rats 4, 8, or 14 weeks after cord contusion regardless of the extent of SCI. Northern blot complementary DNA (cDNA) hybridization revealed transient but significant decreases in the levels of Sertoli cell-specific transcripts in SCC rats. In addition, levels of messenger RNA (mRNA) transcripts for germ cell-specific transition protein-2 and protamine-1 were consistently decreased in these rats. Such effects were related to the height of the weight drop and were associated with reduced levels of mRNA for cyclic adenosine monophosphate (cAMP) responsive element modulator (CREM). These results demonstrated specific effects of SCI on spermiogenesis and were consistent with altered cAMP signaling in testicular cells after SCI. Sperm motility was also significantly decreased in SCC rats and was related to the height of weight drop. Normal sperm motility recovered only in those rats injured by weight drop from 12.5- and 25-mm heights. In summary, current results demonstrate persistent abnormalities in spermiogenesis and sperm motility in rats that suffered spinal cord contusion by weight drop. Such effects were related to the height of the weight drop and thus to the extent of SCI.

Animals↗

PubMed2001

cAMP response element modulator (CREM): an essential factor for spermatogenesis in primates?

CREM is a cAMP-related transcription factor and alternate promotor usage and splicing generate repressor and activator transcripts of CREM within the testis. CREM activators are highly expressed in post-meiotic haploid germ cells and are essential for spermatid maturation in the mouse model as revealed by gene-targeting studies. Analysis of testicular CREM expression in rodent and monkey species, and in men yielded a highly comparable pattern thus suggesting that CREM is of general importance for spermatid development in the mammalian testis. Also, many CREM target genes have been identified in haploid germ cells. Studies in men with spermatogenic disturbance and spermatid maturation arrest demonstrated abnormal CREM expression and altered splicing events. Collectively, the data strongly argue for an essential role of CREM during spermatid maturation in primates.

Animals↗

PubMed2004

Specialized rules of gene transcription in male germ cells: the CREM paradigm.

Specialized transcription complexes that coordinate the differentiation programme of spermatogenesis have been found in germ cells, which display specific differences in the components of the general transcription machinery. The TATA-binding protein family and its associated cofactors, for example, show upregulated expression in testis. In this physiological context, transcriptional control mediated by the activator cAMP response element modulator (CREM) represents an established paradigm. Somatic cell activation by CREM requires its phosphorylation at a unique regulatory site (Ser117) and subsequent interaction with the ubiquitous coactivator CREB-binding protein. In testis, CREM transcriptional activity is controlled through interaction with a tissue-specific partner, activator of CREM in the testis (ACT), which confers a powerful, phosphorylation-independent activation capacity. The function of ACT was found to be regulated by the testis-specific kinesin KIF17b. Here we discuss some aspects of the testis-specific transcription machinery, whose function is essential for the process of spermatogenesis.

Animals↗

PubMed2006

Regulation of gene expression in post-meiotic male germ cells: CREM-signalling pathways and male fertility.

Spermatogenesis is a remarkably complex process in which diploid spermatogonial stem cells undergo a series of mitotic and meiotic cell divisions to give rise to haploid round spermatids. These haploid cells then go through a dramatic morphological remodelling involving extensive chromatin condensation, reduction in nuclear and cytoplasmic volume, formation of an acrosome system and tail, all of which contribute to the formation of a mature spermatozoon fully capable of fertilizing the oocyte and passing along its genetic information to the next generation. To accomplish such a complex program, an intricate and efficient mechanism is required to finely tune the levels of expression of specific genes necessary for this process. Accordingly, the regulation of gene expression in post-meiotic male germ cells is governed by specific mechanisms unique to these cells. The cyclic adenosine monophosphate (cAMP) response element modulator (CREM) is an essential component of this program, and its activity is regulated through interactions with a germ cell-specific, CREM phosphorylation-independent transcriptional co-activator, activator of CREM in testis (ACT). In turn, the ability of ACT to regulate CREM activity is controlled by a germ cell-specific kinesin, Kif17b, which regulates the subcellular distribution of ACT. Further, the mRNA from CREM target genes interacts with several germ cell-specific RNA-binding proteins, which function to transport and stabilize these mRNAs. This sophisticated and complex regulation of gene expression in post-meiotic germ cells is governed by unique mechanisms specific to these cells and is fundamental to male fertility.

Cyclic AMP Response Element Modulator↗

PubMed1994

Positive regulation of the cAMP-responsive activator CREM by the p70 S6 kinase: an alternative route to mitogen-induced gene expression.

Activation of the adenylyl cyclase signaling pathway elicits the induction of genes via activators binding to cAMP-responsive elements (CREs). Nuclear factor CRE modulator (CREM) is activated by PKA-mediated phosphorylation on a serine at position 117. We show that Ser-117 is also phosphorylated by the mitogen-activated p70 S6 kinase (p70S6K) in vitro. Activation of cellular p70S6K by serum factors enhances Ser-117 phosphorylation and CREM transactivation. Coexpression of p70S6K significantly increases transactivation by a GAL4-CREM fusion. The macrolide rapamycin, a potent and specific inhibitor of p70S6K in vivo, completely blocks CREM activation induced by serum and by p70S6K. Thus, CREM constitutes a target for mitogenic signaling through p70S6K and may acts as a nuclear effector in which transduction pathways may converge and cross-talk.

Amino Acid Sequence↗

PubMed1998

ICER-IIgamma is a tumor suppressor that mediates the antiproliferative activity of cAMP.

The second messenger cAMP inhibits the proliferation of most cell types. The nuclear response of cAMP is mediated by transcription factors like the cAMP-Responsive Element Modulator (CREM) gene. One of the products of the CREM gene, the transcriptional repressor Inducible cAMP Early Repressor-IIgamma (ICER-IIgamma), is induced by cAMP. ICER-IIgamma blocks cells at the G2/M boundary of the cell cycle. Here we show that ICER-IIgamma dramatically inhibits the growth and DNA synthesis of mouse pituitary tumor cells and human choriocarcinoma cells. This alteration in cell growth is coupled with reduced ability of these cells to grow in an anchorage-independent manner and to form tumors in mice. These data demonstrate that ICER-IIgamma is a tumor suppressor gene product mediating the antiproliferative activity of cAMP.

Agar↗

PubMed2006

The viral protein A238L inhibits TNF-alpha expression through a CBP/p300 transcriptional coactivators pathway.

African swine fever virus (ASFV) is able to inhibit TNF-alpha-induced gene expression through the synthesis of A238L protein. This was shown by the use of deletion mutants lacking the A238L gene from the Vero cell-adapted Ba71V ASFV strain and from the virulent isolate E70. To further analyze the molecular mechanism by which the viral gene controls TNF-alpha, we have used Jurkat cells stably transfected with the viral gene to identify the TNF-alpha regulatory elements involved in the induction of the gene after stimulation with PMA and calcium ionophore. We have thus identified the cAMP-responsive element and kappa3 sites on the TNF-alpha promoter as the responsible of the gene activation, and demonstrate that A238L inhibits TNF-alpha expression through these DNA binding sites. This inhibition was partially reverted by overexpression of the transcriptional factors NF-AT, NF-kappaB, and c-Jun. Furthermore, we present evidence that A238L inhibits the activation of TNF-alpha by modulating NF-kappaB, NF-AT, and c-Jun trans activation through a mechanism that involves CREB binding protein/p300 function, because overexpression of these transcriptional coactivators recovers TNF-alpha promoter activity. In addition, we show that A238L is a nuclear protein that binds to the cyclic AMP-responsive element/kappa3 complex, thus displacing the CREB binding protein/p300 coactivators. Taken together, these results establish a novel mechanism in the control of TNF-alpha gene expression by a viral protein that could represent an efficient strategy used by ASFV to evade the innate immune response.

Activating Transcription Factors↗

PubMed2005

Establishment of a diabetic mouse model with progressive diabetic nephropathy.

Although diabetic animal models exist, no single animal model develops renal changes identical to those seen in humans. Here we show that transgenic mice that overexpress inducible cAMP early repressor (ICER Igamma) in pancreatic beta cells are a good model to study the pathogenesis of diabetic nephropathy. Although ICER Igamma transgenic mice exhibit extremely high blood glucose levels throughout their lives, they survive long enough to develop diabetic nephropathy. Using this model we followed the progress of diabetic renal changes compared to those seen in humans. By 8 weeks of age, the glomerular filtration rate (GFR) was already increased, and glomerular hypertrophy was prominent. At 20 weeks, GFR reached its peak, and urine albumin excretion rate was elevated. Finally, at 40 weeks, diffuse glomerular sclerotic lesions were prominently accompanied by increased expression of collagen type IV and laminin and reduced expression of matrix metalloproteinase-2. Nodular lesions were absent, but glomerular basement membrane thickening was prominent. At this point, GFR declined and urinary albumin excretion rate increased, causing a nephrotic state with lower serum albumin and higher serum total cholesterol. Thus, similar to human diabetic nephropathy, ICER Igamma transgenic mice exhibit a stable and progressive phenotype of diabetic kidney disease due solely to chronic hyperglycemia without other modulating factors.

Albumins↗

PubMed1999

Characterization of the genomic structure of the murine Spam1 gene and its promoter: evidence for transcriptional regulation by a cAMP-responsive element.

The Sperm Adhesion Molecule 1 (SPAM1), also known as PH-20, is a sperm membrane-bound protein that has been shown to have bifunctional roles in fertilization. It is encoded by a gene that is widely conserved in mammalian species, underscoring its importance in the fertilization process. Here we determined the genomic structure of the murine homologue, Spam1, using PCR analysis, and studied its transcriptional regulation. The gene covers approximately 10.5 kb of genomic DNA, is encoded by four exons, and the splice site consensus sequence is maintained in all intron-exon junctions, similar to that reported for the human homologue. With primer extension analysis, two transcription initiation sites were detected. One was assigned to the residue C and the other (a minor site) to the residue G, at positions 1 and -56, respectively. These are at 313 and 369 nucleotides upstream of the translation initiation codon, ATG. In about 770 bp upstream region of Spam1 that has been cloned and sequenced, multiple transcription factor binding sites including a CRE (cAMP-responsive element) were found. We specifically studied the function of the eight nucleotide CRE sequence (TGATGTCA) at -57 (or -62 depending on the strain of mice) of the promoter region. It can bind to the transcription factor CREM (cAMP-responsive element modulator) in gel mobility shift assays using mouse testis nuclear extract, and the binding can be inhibited by a 28 bp oligonucleotide containing the CRE sequence. Similar binding and inhibition assays using rat nuclear extract suggest the existence of a rat CRE sequence and the involvement of CREM in rat Spam1 expression. In vitro transcription assays suggest that CRE is necessary for the transcriptional activity of the murine promoter, and Northern analysis shows that Spam1 transcripts are absent in CREM-knockout mice. The results strongly suggest that the murine Spam1 expression is under the control of CREM, and that this transcriptional regulator for Spam1 might be conserved in other mammals, at least in the rat.

Animals↗

PubMed2000

Photoperiod differentially regulates the expression of Per1 and ICER in the pars tuberalis and the suprachiasmatic nucleus of the Siberian hamster.

Previous studies demonstrated that the clock gene Per1 and the transcription factor ICER are expressed rhythmically in the suprachiasmatic nucleus (SCN) and in the pars tuberalis (PT). In the Syrian hamster the duration of photoperiod affects the amplitude of gene expression in the PT, and melatonin administered before lights-on suppressed the peak of Per1/ICER expression; these effects were not seen in the SCN. It was speculated that the inefficacy of melatonin was due to the low density of melatonin receptors in the SCN of this species. The aim of the present study was to determine whether this phenomenon also occurs in the Siberian hamster, which expresses a higher density of melatonin receptors in the SCN. Male Siberian hamsters were housed in long days (16 h light : 8 h dark) or short days (8 h light : 16 h dark) and expression of Per1 and ICER mRNA was studied by in situ hybridization. The expression of Per1 and ICER mRNA in the PT peaked 3 h following lights-on (ZT3) under both photoperiods. The amplitudes of these peaks were greatly attenuated under short photoperiod. In the SCN, the duration of Per1 gene expression was proportional to the length of the light phase, but only a modest amplitude effect was observed. Injections of melatonin (25 microg) 1 h before lights-on significantly reduced the expression of both genes in the PT at ZT3, but had no effect in the SCN. These data demonstrate that photoperiod-dependent amplitude modulation of Per1 and ICER gene expression in the PT is conserved across species, and reinforce the argument that this phenomenon is driven by melatonin.

Animals↗

PubMed2000

Marmoset spermatogenesis: organizational similarities to the human.

The common marmoset (Callithrix jacchus), a small New World primate of high fecundity, is widely used in reproductive research. The aim of the present study was to determine the organization of the germ cells within the seminiferous epithelium, the duration of the spermatogenic cycle and the number of spermatogonial mitoses. Antibodies to cAMP response element modulator (CREM) and proliferating nuclear cell antigen (PCNA) and a cRNA directed against protamine P2 and morphological criteria were used to discriminate between stages of the spermatogenic cycle. Plastic sections were used to document the cell associations present in each of the nine stages of spermatogenesis. Up to five such stages could be observed within individual cross-sections of seminiferous tubules. Based on the pattern of incorporation of bromodeoxyuridine the length of the spermatogenic cycle was estimated to be 10 days and the duration of spermatogenesis to be 37 days. Four mitotic divisions were noted in spermatogonia. It is concluded that the organization of spermatogenesis in the marmoset has similarities to the human ('helical') and this makes the marmoset a suitable model for studies relevant to human testicular function.

Animals↗