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PubMed1994

A developmental study of cyclic AMP-response element binding protein (CREB) by in situ hybridization histochemistry and immunocytochemistry in the rat neocortex.

Cyclic AMP (cAMP) mediates the hormonal stimulation of a number of eukaryotic genes by directing the protein kinase A (PK-A)-dependent phosphorylation of the transcription factor CREB. Somatostatin is one such gene known to be transcriptionally activated by cAMP via CREB. In view of the role somatostatin plays in the regulation of neocortical development, we examined the early expression of CREB mRNA and protein (from E10 to E14) in the rat neocortex by in situ hybridization and immunocytochemistry. mRNA for CREB was detected in all layers of the developing neocortex from E10 to E14. CREB immunoreactivity (CREB-IR) was also observed in most cortical cells by E10. However, the number of CREB-immunoreactive nuclei decreased thereafter, and on E14 there were immunoreactive cells only in the preplate. A moderate amount of somatostatin mRNA was observed on E16 in layer I, which is produced from the preplate. This stage specific expression of the CREB protein in the developing neuroepithelium suggests that by regulating transcription of some peptides including somatostatin, CREB plays a role in cortical development.

Animals↗
PubMed1992

The transcription factors c-JUN, JUN D and CREB, but not FOS and KROX-24, are differentially regulated in axotomized neurons following transection of rat sciatic nerve.

In adult rats, expression of c-JUN, JUN B, JUN D, c-FOS, FOS B, KROX-24 and CREB proteins was investigated by immunocytochemistry in L4 and L5 dorsal root ganglia and lumbar spinal cord for up to 300 days following transection of the left sciatic nerve. In dorsal root ganglia, expressions of c-JUN and JUN D were increased 10 h and 15 h after sciatic nerve transection, respectively. c-JUN was still at an elevated level after 300 days predominantly in small diameter neurons, whereas JUN D had declined to control levels after 100 days. In contrast to the JUN proteins, expression of CREB showed a delayed onset after 10 days and reached a maximum between 70 and 150 days. In motoneurons, expression of c-JUN and JUN D was increased 15 h and 25 h after sciatic nerve transection, respectively. Expression of c-JUN remained increased after 150 days, whereas JUN D had declined to control levels after 70 days. In contrast, expression of CREB declined within 30 h in axotomized motoneurons and remained on a reduced level for up to 150 days. JUN B, c-FOS, FOS B and KROX-24 were not induced either following axotomy or following a repeated nerve crush. Sciatic nerve transection including the surgical procedure transynaptically provoked a transient expression of all JUN, FOS and KROX-24 proteins in neurons of spinal dorsal horn which disappeared after 5 days except the expression of JUN D which lasted for up to 20 days. In contrast, CREB immunoreactivity was not at all altered in neurons of spinal dorsal horn. In untreated animals, CREB and to a lesser extent JUN D showed an ubiquitous expression in neurons and glia cells of spinal cord, whereas expression of c-JUN and a weak expression of FOS B were restricted to motoneurons. In neurons of the dorsal root ganglia, a basal expression was found for c-JUN, JUN D and CREB and, at a low level, for FOS B and KROX-24. c-JUN and JUN D were colocalized with CREB in many cells such as interneurons, motoneurons, dorsal root ganglion cells and glial cells indicating the possibility for both the control of c-jun and jun D expression by CREB and the competition of JUN and CREB proteins for CRE consensus sequences.

Animals↗
PubMed2006

The cAMP response element binding protein (CREB) as an integrative HUB selector in metazoans: clues from the hydra model system.

In eukaryotic cells, a multiplicity of extra-cellular signals can activate a unique signal transduction system that at the nuclear level will turn on a variety of target genes, eliciting thus diverse responses adapted to the initial signal. How distinct signals can converge on a unique signalling pathway that will nevertheless produce signal-specific responses provides a theoretical paradox that can be traced back early in evolution. In bilaterians, the CREB pathway connects diverse extra-cellular signals via cytoplasmic kinases to the CREB transcription factor and the CBP co-activator, regulating according to the context, cell survival, cell proliferation, cell differentiation, pro-apoptosis, long-term memory, hence achieving a "hub" function for cellular and developmental processes. In hydra, the CREB pathway is highly conserved and activated during early head regeneration through RSK-dependent CREB phosphorylation. We show here that the CREB transcription factor and the RSK kinase are co-expressed in all three hydra cell lineages including dividing interstitial stem cells, proliferating nematoblasts, proliferating spermatogonia and spermatocytes, differentiating and mature neurons as well as ectodermal and endodermal myoepithelial cells. In addition, CREB gene expression is specifically up-regulated during early regeneration and early budding. When the CREB function was chemically prevented, the early post-amputation induction of the HyBraI gene was no longer observed and head regeneration was stacked. Thus, in hydra, the CREB pathway appears already involved in multiple tasks, such as reactivation of developmental programs in an adult context, self-renewal of stem cells, proliferation of progenitors and neurogenesis. Consequently, the hub function played by the CREB pathway was established early in animal evolution and might have contributed to the formation of an efficient oral pole through the integration of the neurogenic and patterning functions.

Animals↗
PubMed2005

Serum/glucocorticoid-inducible kinase can phosphorylate the cyclic AMP response element binding protein, CREB.

To maintain homeostasis, cells often respond to stressful extra-cellular stimuli by new gene expression. Serum/glucocorticoid-induced kinase (SGK) is an immediate early gene whose expression is induced by a variety of extra-cellular stimuli. Here, we examine the possibility that SGK can directly phosphorylate the transcription factor cyclic AMP response element binding protein (CREB). In a cell-free context, SGK physically associates with CREB and SGK phosphorylates it on serine 133. Phospho-serine 133 is essential for stimulating the transcriptional activity of CREB. Further, we show that in a variety of cellular contexts, SGK phosphorylates CREB. Activation of receptor tyrosine kinase pathways or the phosphoinositide-dependent kinase 1 (PDK1) lead to SGK-dependent CREB phosphorylation. Hormonal stimulation of epithelial cells leads to the induction of endogenous SGK and CREB phosphorylation. A dominant-negative form of SGK blocks dexamethasone-induced CREB phosphorylation. Our studies indicate that stimulation of SGK can lead to CREB phosphorylation, suggesting that CREB-dependent gene transcription is an important link between stressful extra-cellular signals and cellular responses.

Animals↗
PubMed2003

TORCs: transducers of regulated CREB activity.

The cAMP responsive factor CREB stimulates gene expression, following its phosphorylation at Ser133, via recruitment of the coactivator CBP. In certain cell types, CREB also functions as a constitutive activator, although the underlying mechanisms are not understood. Here, we characterize a conserved family of coactivators, designated TORCs, for Transducers of Regulated CREB activity, that enhances CRE-dependent transcription via a phosphorylation-independent interaction with the bZIP DNA binding/dimerization domain of CREB. TORC recruitment does not appear to modulate CREB DNA binding activity, but rather enhances the interaction of CREB with the TAF(II)130 component of TFIID following its recruitment to the promoter. Remarkably, in certain mucoepidermoid carcinomas, a chromosomal translocation fuses the CREB binding domain of TORC1 to the Notch coactivator Mastermind (MAML2). As expression of the TORC1-MAML2 chimera strongly induced target gene expression via CREB, our results reveal a mechanism by which CREB stimulates transcription in normal and transformed cells.

Amino Acid Sequence↗
PubMed2003

Intrathecal injection of cAMP response element binding protein (CREB) antisense oligonucleotide attenuates tactile allodynia caused by partial sciatic nerve ligation.

The transcription factor cAMP responsive element binding protein (CREB) is important in regulating immediate-early genes and some late-effector genes involved in neuroplasticity in response to peripheral injury and stressful insults. Partial nerve injury elicited neuropathic pain is accompanied by increased phosphorylation of CREB in the ipsilateral spinal cord dorsal horn (Ma and Quirion, Pain 93 (2001) 295; Miletic et al., Pain 99 (2002) 493). The aim of this study is to determine whether increased phosphorylation of CREB in the dorsal horn contributes to the pathogenesis of neuropathic pain. Three weeks following partial sciatic nerve ligation (PSNL), daily intrathecal injection of antisense CREB oligodeoxynucleotide (ODN, 20 microg/day) for 5 days significantly attenuated tactile allodynia. The attenuation lasted for more than 4 days. Total CREB and phosphorylated CREB in both ipsilateral and contralateral dorsal horn neurons were dramatically reduced in antisense ODN injected PSNL rats 1 week after injection. The extent of reduction of total CREB and phosphorylated CREB containing cells in the dorsal horn ipsilateral to injury was greater than in the contralateral dorsal horn. These data suggest that phosphorylation of CREB is an important contributing event in the central plasticity of nerve injury and in the pathogenesis of neuropathic pain.

Animals↗
PubMedDate not supplied

Differential effects of fluoxetine and imipramine on the phosphorylation of the transcription factor CREB and cell-viability.

It has been shown that antidepressants increase the expression of CREB (cAMP-response-element-binding-protein) and BDNF (brain derived neurotrophic factor) in vivo. Apparently inconsistent to these survival-promoting properties for many years antidepressants are known to induce apoptosis in various cell types in vitro. In the present study we evaluated if the antidepressants imipramine and fluoxetine are capable to influence the translational expression and phosphorylation of CREB (pCREB) in cells known to be apoptosis-inducible by antidepressants. We therefore used jurkat cells and quantified apoptosis via propidiumiodid-staining and FACS-analysis. CREB-expression and -phosphorylation was quantified via western blot. Both antidepressants induced apoptosis within 24 h. Fluoxetin starts to induce significant apoptosis at a concentration of 20 microM, whereas imipramine at 100 microM. At these concentrations both antidepressants also increased the phosphorylation of CREB within 6 h. But even in concentrations to low to induce apoptosis both antidepressants still increased CREB-phosphorylation. Treating cells with lowest concentrations only imipramine revealed an increase of CREB-phosphorylation after long-time treatment over 3 weeks. In all experiments overall CREB-expression remained unchanged. In conclusion our experiments indicate that antidepressants are capable to increase CREB-phosphorylation without induction of apoptosis depending on concentration and duration of treatment. We further assume that antidepressants induce CREB-phosphorylation via signal transduction pathways that are different from those inducing apoptosis.

Antidepressive Agents, Second-Generation↗
PubMed2002

Coupling of extrasynaptic NMDA receptors to a CREB shut-off pathway is developmentally regulated.

Electrical activation of hippocampal neurons can cause calcium influx through different entry sites which may specify nuclear signalling and induction of gene transcription and downstream physiological outputs. Genomic responses initiated by NMDA receptors (NMDARs) are critically dependent on whether synaptically or extrasynaptically located receptors are stimulated; calcium flux through synaptic NMDARs activates CREB whereas flux through extrasynaptic NMDARs triggers a CREB shut-off signal. Here we investigated the possibility that the coupling of extrasynaptic NMDARs to the CREB shut-off pathway is regulated during in vitro development. Cultured hippocampal neurons were analyzed after 7 or 12 days of in vitro culturing. We found that synaptic NMDAR activity induced CREB phosphorylation at day in vitro (DIV) 7 and DIV 12. In contrast, the extrasynaptic NMDAR-dependent CREB shut-off signal is developmentally regulated. At DIV 12 extrasynaptic NMDAR activation shuts down CREB and overrides the CREB-activating signal triggered by synaptic NMDAR activation. In contrast, at DIV 7 this shut off signal is absent; both synaptic and extrasynaptic NMDARs activate CREB function. Developmental changes in NMDAR signaling have been proposed to contribute to the emergence of glutamate excitotoxicity, which causes apoptosis or necrosis depending on the severity of the insult. Since CREB regulates a number of pro-survival genes, the emergence of this shut-off around DIV 7 may contribute to the increase in susceptibility of neurons to glutamate-induced neuropathology in vitro and in vivo during post-natal development.

Animals↗
PubMed2004

Modulation of anxiety-like behavior and morphine dependence in CREB-deficient mice.

The transcription factor cAMP-responsive element binding protein (CREB) has been shown to regulate different physiological responses including drug addiction and emotional behavior. Molecular changes including adaptive modifications of the transcription factor CREB are produced during drug dependence in many regions of the brain, including the locus coeruleus (LC), but the molecular mechanisms involving CREB within these regions have remained controversial. To further investigate the involvement of CREB in emotional behavior, drug reward and opioid physical dependence, we used two independently generated CREB-deficient mice. We employed the Cre/loxP system to generate mice with a conditional CREB mutation restricted to the nervous system, where all CREB isoforms are lacking in the brain (Crebl(NesCre)). A genetically defined cohort of the previously described hypomorphic Crebl(alphadelta) mice, in which the two major transcriptionally active isoforms (alpha and delta) are disrupted throughout the organism, were also used. First, we investigated the responses to stress of the CREB-deficient mice in several paradigms, and we found an increased anxiogenic-like response in the both Creb1 mutant mice in different behavioral models. We investigated the rewarding properties of drugs of abuse (cocaine and morphine) and natural reward (food) using the conditioned place-preference paradigm. No modification of motivational responses of morphine, cocaine, or food was observed in mutant mice. Finally, we evaluated opioid dependence by measuring the behavioral expression of morphine withdrawal and electrophysiological recordings of LC neurons. We showed an important attenuation of the behavioral expression of abstinence and a decrease in the hyperactivity of LC neurons in both Creb1 mutant mice. Our results emphasize the selective role played by neuronal CREB in emotional-like behavior and the somatic expression morphine withdrawal, without participating in the rewarding properties induced by morphine and cocaine.

Analysis of Variance↗
PubMed2003

Transcriptional regulation of the promoter of the rat frizzled related protein gene by CREB.

Frizzled related proteins (Frps) are secreted proteins structurally similar to frizzled receptors; they bind Wnt via the cysteine-rich domain and antagonize the Wnt signaling pathway. In this study, we have investigated the mechanisms regulating the transcriptional regulation of rat Frp (rFrp) promoter. From previous findings, we know that the transcriptional activation domain of rFrp resides in the region -202 to -144 relative to the transcription start site, and that it is essential for efficient promoter activity. The study presented here was designed to identify trans-acting factors that bind to this critical domain of the rFrp promoter and to elucidate the pathway involved in the regulation of rFrp expression. Electrophoretic mobility shift assay (EMSA) demonstrated that specific DNA-protein binding activities fall into two adjacent core sequences with (CTTTGGGGG) at -197 to -189 and (AGATGATGTAA) at -151 to -141 of the rFrp promoter. Reporter assay showed that these core sequences are both required for the activation of rFrp promoter. Mutation within either one or both core sequence drastically reduced the promoter activity. Southwestern blotting showed that the estimated molecular mass of the distinct binding protein to the (AGATGATGTAA) domain is about 43 kDa. Further EMSA suggested CREB as the trans-acting factor in the DNA-protein complex, which was out competed by CREB consensus oligonucleotides and supershifted by anti-CREB antibody. Overexpression of PKA and CREB also transactivated rFrp promoter, and dominant-negative CREB inhibited the promoter activity in transient reporter assays. More importantly, CREB, phosphorylated CREB and the adaptor protein CBP were found binding to the endogenous rFrp promoter using chromatin immunoprecipitation assay. Collectively, our results demonstrate the induction of rFrp promoter activity by PKA and CREB in vitro, and the binding of CREB and CBP to the rFrp promoter core motif in vivo.

Animals↗
PubMed1999

Cyclic AMP-dependent activation of the proenkephalin gene requires phosphorylation of CREB at serine-133 and a Src-related kinase.

The transcription factor CREB [cyclic AMP response element (CRE)-binding protein] is activated by several kinase pathways on phosphorylation of serine-133. Phosphorylation of CREB at serine-133 is required for the induction of target gene expression. The proenkephalin gene is a target of cyclic AMP-dependent agonists like forskolin, and its expression is driven by the enhancer element CRE-2. It has been shown that CREB binds CRE-2 in extracts from striatum and hypothalamus. However, these studies did not show a functional requirement for CREB serine-133 phosphorylation in CRE-2 function. We demonstrate that CREB binds CRE-2 in primary astrocyte cultures and that transcriptional activation of CRE-2 requires CREB phosphorylation at serine-133. In addition, it has recently been shown that, at least in some contexts, CREB phosphorylation is not sufficient to activate target gene expression and that another intracellular signal seems to be required. Therefore, we also sought to determine if another signaling event, in addition to CREB phosphorylation, might be involved in cyclic AMP-mediated induction of the proenkephalin gene. We have found that the inhibition of src-related nonreceptor tyrosine kinases blocks forskolin-induced proenkephalin gene expression without having any effect on serine-133-phosphorylated CREB levels and that constitutively activated src kinase can activate the proenkephalin promoter.

Animals↗
PubMed2003

Small ubiquitin-related modifier-1 modification mediates resolution of CREB-dependent responses to hypoxia.

Phosphorylation-dependent ubiquitination combined with proteasomal degradation of transcriptional regulators is a recently appreciated mechanism for control of a number of inflammatory genes. Far less is known about the counterregulatory mechanisms that repress transcriptional activity in these pathways during resolution. Here, we investigated the transient nature of hypoxia-induced tumor necrosis factor (TNF)alpha in T84 cells, a process we have previously shown to involve phosphorylation-dependent degradation of the cAMP-response element-binding protein (CREB). Initial studies indicate hypoxia-induced TNFalpha to be a transient event, the resolution of which is associated with the appearance of a higher molecular weight modified form of CREB. Gene array analysis of mRNA derived from hypoxic cells identified a time-dependent induction of small ubiquitin-related modifier (SUMO)-1 mRNA. In prolonged hypoxia, CREB is posttranslationally modified by SUMO-1. Furthermore, SUMO-1 overexpression stabilizes CREB in hypoxia and enhances CREB-dependent reporter gene activity. Site-directed mutagenesis of lysine residues K285 and K304 identifies them as SUMO acceptors in vivo and in vitro. Mutation of K304 also results in loss of CREB nuclear localization, implying a role for SUMO-1 modification at this site in the subcellular localization of CREB. Thus, in prolonged hypoxia, CREB is modified by association with SUMO-1. Furthermore, we hypothesize that such an event stabilizes and promotes nuclear localization of CREB and thus complements an endogenous resolution phase for hypoxia-induced inflammatory processes.

Amino Acid Motifs↗
PubMed2002

CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli.

The transcription factor cAMP response element (CRE)-binding protein (CREB) has been shown to regulate neural plasticity. Drugs of abuse activate CREB in the nucleus accumbens, an important part of the brain's reward pathways, and local manipulations of CREB activity have been shown to affect cocaine reward, suggesting an active role of CREB in adaptive processes that follow exposure to drugs of abuse. Using CRE-LacZ reporter mice, we show that not only rewarding stimuli such as morphine, but also aversive stimuli such as stress, activate CRE-mediated transcription in the nucleus accumbens shell. Using viral-mediated gene transfer to locally alter the activity of CREB, we show that this manipulation affects morphine reward, as well as the preference for sucrose, a more natural reward. We then show that local changes in CREB activity induce a more general syndrome, by altering reactions to anxiogenic, aversive, and nociceptive stimuli as well. Increased CREB activity in the nucleus accumbens shell decreases an animal's responses to each of these stimuli, whereas decreased CREB activity induces an opposite phenotype. These results show that environmental stimuli regulate CRE-mediated transcription within the nucleus accumbens shell, and that changes in CREB activity within this brain area subsequently alter gating between emotional stimuli and their behavioral responses. This control appears to be independent of the intrinsic appetitive or aversive value of the stimulus. The potential relevance of these data to addiction and mood disorders is discussed.

Animals↗
PubMed2001

CREB-H: a novel mammalian transcription factor belonging to the CREB/ATF family and functioning via the box-B element with a liver-specific expression.

The expression of liver-specific genes is regulated by unequivocally allocated transcription factors via proper responsible elements within their promoters. We identified a novel transcription factor, CREB-H, and found that its expression was restricted in the liver among 16 human tissues tested. A region of CREB-H exhibited significant homology to the basic leucine zipper (b-Zip) domain of members of the CREB/ATF family: mammalian LZIP and Drosophila BBF-2 that binds to box-B, a Drosophila enhancer modulating the fat-body-specific gene expression. CREB-H contained a hydrophobic region representing a putative transmembrane domain, like LZIP. Constructing a variety of CREB-H fusion proteins with the GAL4 DNA-binding domain disclosed that CREB-H functioned as a transcriptional activator and its N-terminal 149 amino acids accounted for the activation ability. Gel mobility sift assays revealed that CREB-H did not bind to the C/EBP, AP-1 and NF-kappaB elements but specifically bound to CRE and the box-B element. Luciferase reporter assays demonstrated that like BBF-2, CREB-H activated transcription via the box-B element and that a deletion of the putative transmembrane domain increased the activation of reporter expression significantly. Furthermore, a fusion protein of GFP and full-length CREB-H was localized in reticular structures surrounding the nucleus, whereas a fusion protein of GFP and a deletion mutant lacking the putative transmembrane domain was mainly in the nucleus. These findings suggest that CREB-H plays an important role in transcriptional regulation of genes specifically expressed in the liver, and that the putative transmembrane domain may be associated with modulation of its function as the transcriptional activator.

Activating Transcription Factors↗
PubMed2004

Neurotrophin-3 and a CREB-mediated signaling pathway regulate Bcl-2 expression in oligodendrocyte progenitor cells.

Our previous results suggested that the transcription factor CREB mediates the actions of neuroligands and growth factor signals that coupled to different signaling pathways may play different roles along oligodendrocyte (OLG) development. We showed before that CREB phosphorylation in OLG progenitors is up-regulated by neurotrophin-3 (NT-3); and moreover CREB is required for NT-3 to stimulate the proliferation of these cells. We now show that treatment of OLG progenitors with NT-3 is also accompanied by an increase in the levels of the anti-apoptotic protein Bcl-2. Interestingly, the presence of a putative CREB binding site (CRE) in the Bcl-2 gene raised the possibility that CREB could also be involved in regulating Bcl-2 expression in the OLGs. Supporting this hypothesis, the NT-3 dependent increase in Bcl-2 levels is abolished by inhibition of CREB expression. In addition, transient transfection experiments using various regions of the Bcl-2 promoter and mutation of the CRE site indicate a direct role of CREB in regulating Bcl-2 gene activity in response to NT-3. Furthermore, protein-DNA binding assays show that the CREB protein from freshly isolated OLGs indeed binds to the Bcl-2 promoter CRE. Together with our previous results, these observations suggest that CREB may play an important role in linking proliferation and survival pathways in the OLG progenitors.

Activating Transcription Factor 1↗
PubMed2004

Impaired CREB-1 phosphorylation in antifolate-resistant cell lines with down-regulation of the reduced folate carrier gene.

The human reduced folate carrier (hRFC) is the dominant transporter for the uptake of antifolates used in cancer chemotherapy. We have shown recently that decreased cAMP-responsive element (CRE)-dependent transcription contributes to the loss of hRFC gene expression in multiple antifolate-resistant cell lines. This was associated with markedly decreased levels of phosphorylated cAMP response element-binding protein 1 (pCREB-1) and CRE-binding. Consistent with the autoregulation of CREB-1 gene expression by pCREB-1, prominently decreased CREB-1 mRNA levels were observed in antifolate-resistant cells. We therefore explored the possibility that these cells were defective in CREB-1 phosphorylation, thereby resulting in down-regulation of some cAMP-responsive genes. Two-dimensional gel electrophoresis revealed that CREB-1 and its phosphoisoforms were markedly decreased in these cells. Treatment with forskolin, an activator of adenylyl cyclase, restored both CREB-1 and pCREB-1 levels; this resulted in the restoration of CRE-binding, CRE-reporter activity, and CREB-1 and RFC mRNA levels. Hence, the protein kinase A pathway was examined using various agents that augment intracellular cAMP levels, including cholera toxin, an upstream agonist that renders stimulatory G-proteins (Galphas) constitutively active. Treatment of antifolate-resistant cells with these agents resulted in the restoration of pCREB-1 levels and CRE-reporter activity. Furthermore, transient transfection with a constitutively transcriptionally active VP16-CREB-1 that does not require phosphorylation for its activity resulted in restoration of CREB mRNA levels but not pCREB-1 levels. This is the first demonstration that resistance to various antifolates may potentially be associated with impaired activity of Galphas or their coupled receptors, resulting in loss of CREB-1 phosphorylation and consequent down-regulation of cAMP-responsive genes.

1-Methyl-3-isobutylxanthine↗
PubMed2006

Human T-cell leukemia virus type 1 (HTLV-1) bZIP protein interacts with the cellular transcription factor CREB to inhibit HTLV-1 transcription.

The complex human T-cell leukemia virus type 1 (HTLV-1) retrovirus encodes several proteins that are unique to the virus within its 3'-end region. Among them, the viral transactivator Tax and posttranscriptional regulator Rex are well characterized, and both positively regulate HTLV-1 viral expression. Less is known about the other regulatory proteins encoded in this region of the provirus, including the recently discovered HBZ protein. HBZ has been shown to negatively regulate basal and Tax-dependent HTLV-1 transcription through its ability to interact with specific basic-leucine zipper (bZIP) proteins. In the present study, we found that HBZ reduces HTLV-1 transcription and virion production. We then characterized the interaction between HBZ and the cellular transcription factor CREB. CREB plays a critical role in Tax-mediated HTLV-1 transcription by forming a complex with Tax that binds to viral cyclic AMP-response elements (CREs) located within the viral promoter. We found that HBZ and CREB interact in vivo and directly in vitro, and this interaction occurs through the bZIP domain of each protein. We also found that CREM-Ia and ATF-1, which share significant homology in their bZIP domains with the bZIP domain of CREB, interact with HBZ-bZIP. The interaction between CREB and HBZ prevents CREB binding to the viral CRE elements in vitro and in vivo, suggesting that the reduction in HTLV-1 transcription by HBZ is partly due to the loss of CREB at the promoter. We also found that HBZ displaces CREB from a cellular CRE, suggesting that HBZ may deregulate CREB-dependent cellular gene expression.

Animals↗
PubMed1995

Impaired cyclic AMP-dependent phosphorylation renders CREB a repressor of C/EBP-induced transcription of the somatostatin gene in an insulinoma cell line.

Transcription factor CREB regulates cyclic AMP (cAMP)-dependent gene expression by binding to and activating transcription from cAMP response elements (CREs) in the promoters of target genes. The transcriptional transactivation functions of CREB are activated by its phosphorylation by cAMP-dependent protein kinase A (PKA). In studies of many different phenotypically distinct cells, the CRE of the somatostatin gene promoter is a prototype of a highly cAMP-responsive element regulated by CREB. We now report on a somatostatin-producing rat insulinoma cell line, RIN-1027-B2, in which transcription from the somatostatin gene promoter is paradoxically repressed by CREB. We find that CREB fails to transactivate a CRE-containing somatostatin-chloramphenicol acetyltransferase reporter even when coexpressed with the catalytic subunit of PKA. CAAT box/enhancer-binding protein beta (C/EBP beta) and C/EBP-related activating transcription factor bind to the CRE in the promoter of the somatostatin gene and transactivate transcription. CREB binds competitively with C/EBP beta to the somatostatin CRE in vitro and represses C/EBP beta-induced transcription of the CRE-containing somatostatin-chloramphenicol acetyltransferase reporter. The lack of CREB-mediated transcriptional stimulation is due to the presence of a heat-stable inhibitor of PKA that prevents activation of PKA and subsequent CREB phosphorylation in the nucleus. These findings indicate that dephosphorylated CREB is a negative regulator of C/EBP-activated transcription of the somatostatin gene promoter in RIN-1027-B2 cells.

Activating Transcription Factor 4↗