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PubMed1997

CREB controls LAP/C/EBP beta transcription.

LAP/C/EBP beta is a member of the C/EBP family of transcription factors and is involved in hepatocyte-specific gene expression. Recently we showed that, besides its posttranscriptional regulation, LAP/C/EBP beta mRNA is modulated during liver regeneration. Therefore, in this study we investigated mechanisms which control LAP/C/EBP beta gene transcription. Deletion analysis of the 5'-flanking region, located upstream of the start site of transcription in the LAP/C/EBP beta gene, demonstrated that a small region in close proximity to the TATA box is important in maintaining a high level of transcription of the luciferase reporter gene constructs. In gel shift experiments two sites were identified which are important for specific complex formation within this region. Further analysis by cross-linking, super shift, and competition experiments was performed with liver cell nuclear extracts, hepatoma cell nuclear extracts, or recombinant CREB protein. These experiments conclusively demonstrated that CREB binds to both sites in the LAP/C/EBP beta promoter with an affinity similar to that with the CREB consensus sequence. Transfection experiments with promoter constructs where the CREB sites were mutated showed that these sites are important to maintain both basal promoter activity and LAP/C/EBP beta inducibility through CREB. Northern blot analysis and runoff transcription assays demonstrated that the protein kinase A pathway not only stimulated the activity of the luciferase reporter construct but also the transcription of the endogenous LAP/C/EBP beta gene in different cell types. Western blot analysis of rat liver cell nuclear extracts and runoff transcription assays of rat liver cell nuclei after two-thirds hepatectomy showed a functional link between the induction of CREB phosphorylation and LAP/C/EBP beta mRNA transcription during liver regeneration. These results demonstrate that the two CREB sites are important to control LAP/C/EBP beta transcription in vivo. As several pathways control CREB phosphorylation, our results provide evidence for the transcriptional regulation of LAP/C/EBP beta via CREB under different physiological conditions.

Animals↗
PubMed1997

Anchoring of CREB binding protein to the human T-cell leukemia virus type 1 promoter: a molecular mechanism of Tax transactivation.

The human T-cell leukemia virus type 1 (HTLV-1)-encoded Tax protein activates viral transcription through interaction with the cellular transcription factor CREB (cyclic AMP response element [CRE] binding protein). Although Tax stabilizes the binding of CREB to the Tax-responsive viral CREs in the HTLV-1 promoter, the precise molecular mechanism by which Tax mediates strong transcriptional activation through CREB remains unclear. In this report, we show that Tax promotes high-affinity binding of the KIX domain of CREB binding protein (CBP) to CREB-viral CRE complexes, increasing the stability of KIX in these nucleoprotein complexes by up to 4.4 kcal/mol. Comparable KIX binding affinities were measured for both phosphorylated and unphosphorylated forms of CREB, and in all cases high-affinity binding was dependent upon both Tax and the viral CRE. Tax also promoted association of KIX to a truncated form of CREB containing only the 73-amino-acid basic leucine zipper (bZIP) domain, indicating that the entire amino-terminal CBP-interacting domain of CREB is nonessential in the presence of Tax. Functional studies upheld the binding studies, as expression of the bZIP domain of CREB was sufficient to support Tax transactivation of HTLV-1 transcription in vivo. Finally, we show that transfection of a KIX expression plasmid, which lacks activation properties, inhibited Tax transactivation in vivo. This suggests that KIX occupies the CBP binding site on Tax, and therefore CBP is likely a cofactor in mediating Tax stimulation of HTLV-1 transcription. Together, these data support a model in which Tax anchors CBP to the HTLV-1 promoter, with strong transcriptional activation resulting from the CBP-associated activities of nucleosome remodeling and recruitment of the general transcription machinery.

Activating Transcription Factor 1↗
PubMed2003

Synergism between calcium and cyclic GMP in cyclic AMP response element-dependent transcriptional regulation requires cooperation between CREB and C/EBP-beta.

Calcium induces transcriptional activation of the fos promoter by activation of the cyclic AMP response element (CRE)-binding protein (CREB), and in some cells its effect is enhanced synergistically by cyclic GMP (cGMP) through an unknown mechanism. We observed calcium-cGMP synergism in neuronal and osteogenic cells which express type II cGMP-dependent protein kinase (G-kinase); the effect on the fos promoter was mediated by the CRE and proportional to G-kinase activity. Dominant negative transcription factors showed involvement of CREB- and C/EBP-related proteins but not of AP-1. Expression of C/EBP-beta but not C/EBP-alpha or -delta enhanced the effects of calcium and cGMP on a CRE-dependent reporter gene. The transactivation potential of full-length CREB fused to the DNA-binding domain of Gal4 was increased synergistically by calcium and cGMP, and overexpression of C/EBP-beta enhanced the effect, while a dominant negative C/EBP inhibited it. With a mammalian two-hybrid system, coimmunoprecipitation experiments, and in vitro binding studies, we demonstrated that C/EBP-beta and CREB interacted directly; this interaction involved the C terminus of C/EBP-beta but occurred independently of CREB's leucine zipper domain. CREB Ser(133) phosphorylation was stimulated by calcium but not by cGMP; in cGMP-treated cells, (32)PO(4) incorporation into C/EBP-beta was decreased and C/EBP-beta/CRE complexes were increased, suggesting regulation of C/EBP-beta functions by G-kinase-dependent dephosphorylation. C/EBP-beta and CREB associated with the fos promoter in intact cells, and the amount of promoter-associated C/EBP-beta was increased by calcium and cGMP. We conclude that calcium and cGMP transcriptional synergism requires cooperation of CREB and C/EBP-beta, with calcium and cGMP modulating the phosphorylation states of CREB and C/EBP-beta, respectively.

3T3 Cells↗
PubMed2003

Genetic evidence for a role of CREB in sustained cortical arousal.

The cyclic AMP-response element binding protein (CREB) is an activity-dependent transcription factor important for synaptic plasticity and memory storage. Levels of phosphorylated CREB within the cortex are higher in waking than in sleep, suggesting that CREB plays a role in sleep/wake regulation in mammals. We tested the hypothesis that CREB is critical for sleep/wake regulation by examining behavioral state parameters in mice lacking the alpha and Delta isoforms of CREB. Over 24 h, time spent awake was significantly decreased in CREB alphaDelta mutant mice by approximately 100 min, and time spent in nonrapid eye movement sleep (NREM) sleep was increased correspondingly. Wake and REM sleep periods were shorter in CREB alphaDelta mice, and CREB alphaDelta mice had decreased levels of -activity during wake and REM sleep, consistent with an impairment in the ability to maintain an activated electroencephalogram. These results suggest that the CREB protein contributes to the mechanisms by which wakefulness is maintained and demonstrate that specific genetic alterations in species as diverse as Drosophila and mice produce similar phenotypes in arousal and wakefulness.

Animals↗
PubMed1997

Glucocorticoids inhibit stress-induced phosphorylation of CREB in corticotropin-releasing hormone neurons of the hypothalamic paraventricular nucleus.

The corticotropin-releasing hormone (CRH) gene contains a perfect palindromic motif in its promoter region that allows binding of the cyclic adenosine monophosphate response element binding protein, CREB. Since previous studies suggest that the CRH gene can be activated by cyclic adenosine monophosphate, we determined whether stress and feedback inhibition by glucocorticoids in CRH-producing neurons in the hypothalamic paraventricular nucleus could be mediated by changes in the phosphorylation of CREB. Antisera to CREB and phospho-CREB Ser133 (PCREB), the active phosphorylated form of CREB, were used for immunohistochemical studies on rat brain. In nonstressed animals CREB immunostaining was confined to the nucleus of cells ubiquitously throughout the hypothalamus, while PCREB immunostaining was discretely localized in magnocellular neurons and only a few cells in the medial parvocellular subdivision of the paraventricular nucleus. Ether and handling stress markedly increased the number of PCREB-labeled neurons in the parvocellular subdivision. Double immunolabeling with CRH antiserum revealed that the majority of hypophysiotropic CRH neurons in stressed animals expressed PCREB. Following systemic administration of dexamethasone (100 micrograms/day) for 2.5 days, PCREB immunostaining was completely abolished in parvocellular CRH-producing neurons after ether or handling stress. Dexamethasone had no apparent effect on CREB immunostaining. These results demonstrate that glucocorticoids suppress CREB phosphorylation in hypophysiotropic CRH neurons and suggest that prevention of CREB phosphorylation is a possible mechanism for feedback inhibition of CRH biosynthesis by glucocorticoids.

Activating Transcription Factor 2↗
PubMed2005

CREB, synapses and memory disorders: past progress and future challenges.

In neurons, appropriate long-term adaptive responses to changes in the environment require the conversion of extracellular stimuli into discrete intracellular signals. Many of these signals involve the regulation of gene expression. The cAMP responsive element binding protein (CREB) is a nuclear transcription factor that modulates transcription of genes containing cAMP responsive elements (CRE sites) in their promoters. CREB is a key part of many intracellular signaling events that critically regulate many neural functions. Numerous studies on invertebrates and vertebrates demonstrate that CREB is critical for long-term memory. Here, we review the key features of CREB-dependent transcription and critically evaluate the data examining the roles of CREB in different forms of plasticity, including long-term memory in mammals. Because learning and memory have been linked to specific types of synaptic plasticity in several species, we also review studies on the role of CREB in long-term facilitation in Aplysia and in hippocampal long-term potentiation (LTP). Several human cognitive disorders have been linked to alterations of CREB-regulated gene expression. Therefore, we explore the possibility of targeting CREB function in developing novel treatment strategies. Finally, we highlight areas of research on CREB that are ripe for further advancement.

Animals↗
PubMed2003

[8-Chloro-adenosine increases the activity of transcription factor CREB by modification of phosphorylation].

BACKGROUND & OBJECTIVE: 8-Chloro-adenosine(8-Cl-Ado) is an anti-tumor drug,which has been investigated and developed recently in China. The molecular mechanism of 8-Cl-Ado is now unclear. This study was conducted to investigate the effect of 8-Cl-Ado on the activity of transcription factor cAMP-response-element-binding protein(CREB) and its correlative mechanism in human promyelocytic leukemia cell line HL-60. METHODS: MTT method was used to determine IC(50) (the concentration showing 50% of inhibition rate) of 8-Cl-Ado to HL-60. The protein levels and phosphorylated levels of CREB at different time following 8-Cl-Ado stimulation were examined using Western blot analysis. Gel shift assay was performed to examine DNA binding levels of CREB at different time following 8-Cl-Ado stimulation. RESULTS: (1)The IC(50) of 8-Cl-Ado to HL-60 was about 0.42 micromol/L. (2)8-Cl-Ado increased phosphorylated level of CREB rapidly, which was maximal at 30 minutes, and returned to basal level in 6 hours. The protein level of CREB was constant during 8-Cl-Ado stimulation. (3)8-Cl-Ado did not influence binding level of DNA and CREB. CONCLUSION: The increase of transcriptional activity of CREB induced by 8-Cl-Ado depends on the increased level of phosphorylated CREB, but is not associated with the protein level and DNA binging level of CREB.

2-Chloroadenosine↗
PubMed2006

Dopamine receptors oppositely regulate cocaine-induced transcription factor CREB activation.

OBJECTIVE: To study the role of dopamine receptors in the regulation of the activity of transcription factor cAMP response element-binding protein (CREB) after cocaine treatment. METHODS: By using dopamine receptor antagonists SCH23390 and nafadotride, the activation of CREB by D1 and D3 dopamine receptors after cocaine treatment and role of extracellular signal-regulated kinase (ERK) in cocaine-induced CREB activation were examined by Western blotting, which was also employed for determination of the effect of SCH23390 and nafadotride on CREB activation. RESULTS: D1 receptor antagonist could inhibit cocaine-induced CREB activation, while D3 receptor antagonist enhanced cocaine-induced CREB activation. Dopamine receptor antagonists SCH23390 and nafadotride did not induce CREB activation. SL327, a MEK inhibitor, inhibited cocaine-induced CREB activation. CONCLUSION: D1 and D3 dopamine receptors can oppositely regulate CREB activation after cocaine treatment and this regulation depends on ERK signaling pathway.

Animals↗
PubMed1994

Recombinant cyclic AMP response element binding protein (CREB) phosphorylated on Ser-133 is transcriptionally active upon its introduction into fibroblast nuclei.

To date, it has not been possible to determine whether the single phosphorylation of the cyclic AMP response element binding factor (CREB) at Ser-133 is sufficient for the transcriptional activation by cAMP-mediated pathways. Previous in vivo studies investigating this point have relied upon transfection of cyclic AMP-dependent kinase (cAPK) or its activation by treatment of cells with cell-permeable cAMP analogs. However, as numerous cellular proteins, including CREB, are substrates for activated cAPK, the possibility remains that cAPK substrates other than CREB are required for the transcriptional activity of CRE-containing promoters. To further address this, we compared the activity of recombinant CREB phosphorylated on Ser-133 in both cell-free transcription assays and in vivo after introduction of the same preparations into fibroblasts by microinjection. The activity of phosphorylated CREB, nonphosphorylated CREB, and a mutant form of CREB, containing Ala substituted for Ser at position 133, was found to be nearly identical in cell-free in vitro transcription assays. In contrast, we found that only the phosphorylated CREB microinjected into fibroblasts resulted in the stimulation of expression of CRE-regulated genes. These results suggest that phosphorylation of CREB on Ser-133 directly stimulates its ability to transactivate gene expression in intact cells.

3T3 Cells↗
PubMed1997

17beta-estradiol attenuates CREB decline in the rat hippocampus following seizure.

Cyclic AMP response element-binding protein (CREB) is a transcription factor that has been implicated in the activation of a number of genes. We reported that CREB levels decline following a severe hypoglycemic episode in the hippocampus and cortex in the male rat brain. The present experiment was undertaken to investigate whether 17beta-estradiol prevents the decline in CREB-immunoreactive cells following seizure in female rats. Rats were divided into four groups: ovariectomized (OVX), ovariectomized and insulin-treated (OVX-I), estrogen-replaced (E2), and estrogen-replaced and insulin-treated (E2-I). Generalized seizures were induced by injections with insulin (12.5 IU/kg, intraperitoneally) and animals were recovered by administration of glucose within 5 min of the occurrence of seizure. Control animals were injected with saline instead of insulin. All animals were perfused 90 min after recovery and the brains were processed for CREB immunoreactivity. CREB-positive neurons were counted using a computer-assisted program. Insulin treatment of OVX rats caused a significant decline in CREB-positive neurons in the CA1, CA3, and dentate gyrus compared to OVX rats. Estrogen treatment of OVX rats significantly increased CREB-positive neurons in the CA1 and dentate gyrus and attenuated the insulin-induced decline of CREB-positive neurons in all three regions compared to OVX rats. In conclusion, estrogens appear to induce CREB expression and attenuate its decline in the hippocampus following a severe hypoglycemic episode.

Animals↗
PubMed2005

Inhibition of membrane depolarisation-induced transcriptional activity of cyclic AMP response element binding protein (CREB) by the dual-leucine-zipper-bearing kinase in a pancreatic islet beta cell line.

AIMS/HYPOTHESIS: The activation of the transcription factor cyclic AMP response element binding protein (CREB) by protein kinase A is inhibited by the human orthologue of the mitogen-activated protein kinase, dual-leucine-zipper-bearing kinase (DLK) in teratocarcinoma cells. However, pancreatic beta cells are electrically excitable and a major pathway regulating CREB in these cells is membrane depolarisation, leading to calcium influx and activation of the calcium/calmodulin-dependent protein phosphatase calcineurin. Therefore, the effect of DLK on CREB activity induced by membrane depolarisation was investigated in the beta cell line HIT. MATERIALS AND METHODS: Reporter gene assays and biochemical techniques were used. RESULTS: RT-PCR, Western blot analysis and immunohistochemistry demonstrated the expression of DLK in HIT cells and primary mouse islets. In transient transfection experiments, DLK inhibited both GAL4-CREB activity induced by membrane depolarisation, and transcription directed by the CREB binding site, the cyclic AMP response element. Furthermore, DLK inhibited the transcriptional activity conferred by the CREB coactivator, CREB binding protein, both under basal conditions and after membrane depolarisation. DLK was also effective in response to glucose, the most potent physiological stimulus and known to cause membrane depolarisation of beta cells. Inhibition of calcineurin enhanced DLK activity, whereas overexpression of calcineurin reduced the inhibition by DLK of transcription directed by cyclic AMP response element after membrane depolarisation. CONCLUSIONS/INTERPRETATION: These results demonstrate a calcineurin-sensitive inhibition by DLK of CREB activity after membrane depolarisation in pancreatic islet beta cells. This inhibition may, at least partially, be mediated at the coactivator level. The results thus suggest that DLK plays a role in the regulation of beta cell function, including insulin gene transcription and beta cell apoptosis.

Animals↗
PubMed2006

Enhanced ERK dependent CREB activation reduces apoptosis in staurosporine-treated human neuroblastoma SK-N-BE(2)C cells.

Activation of cAMP response element binding protein (CREB) is implicated in neuronal survival. The mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) activates a transcription factor CREB. Previously, we reported that N-acetyl-O-methyldopamine (NAMDA) protects neurons from ischemia via enhancing ERK dependent CREB phosphorylation. To investigate whether NAMDA induces endogenous survival pathways in apoptotic conditions and whether the neuroprotectant enhances a preexisting survival pathway, we determined the degree of ERK-CREB activation and resistance to apoptosis in staurosporine-treated SK-N-BE(2)C neurons. Compared to forskolin-treated apoptotic cultures, NAMDA-treated cultures induced a minimum activation on ERK (pERK) or CREB (pCREB). However, NAMDA enhanced the activation of ERK and CREB in the presence of forskolin (1.7-fold increase for pCREB, 2.1-fold increase for pERK2, p<0.05 from forskolin). The effect was completely blocked by a specific MEK inhibitor U0126, suggesting the involvement of ERK dependent CREB signaling. Cleavage of caspase-3 and poly-(ADP-ribose)-polymerase was additively reduced in cultures treated with NAMDA and forskolin simultaneously, but not in the presence of U0126. The data showed that NAMDA enhances forskolin-induced ERK-CREB activation and potentiates forskolin-induced resistance to apoptosis. The study indicates that enhancing endogenous survival pathways by NAMDA combined with other neuroprotective measure(s) might be a useful strategy to reduce apoptosis.

Analysis of Variance↗
PubMed2004

Phenylephrine induces activation of CREB in adult rat cardiac myocytes through MSK1 and PKA signaling pathways.

cAMP responsive element binding protein (CREB) is a stimulus induced transcription factor with possible relevance for the pathophysiology of the heart. In the present study, we provide evidence that the hypertrophic agonist, phenylephrine (PE), promotes phosphorylation of CREB in adult rat cardiac myocytes through alpha(1)- and beta-adrenergic receptors. PE-induced phosphorylation of CREB was partially inhibited by Ro318220 and H89, which were shown to be potent inhibitors of mitogen- and stress-activated protein kinase-1 (MSK1) activation, implicating the involvement of this kinase in the response. Similar results were obtained when cardiac myocytes were treated with the inhibitors of ERK1/2 and p38 MAPK pathways. In addition, inhibition of protein kinase A by RpcAMP reduced phosphorylation of CREB, suggesting that this pathway is also involved. Furthermore, PE stimulation was accompanied by an increase in CRE-binding activity, which was reduced by drugs that prevented phosphorylation of CREB. An enhanced CBP/phospho-CREB complex formation was also observed, suggesting recruitment of CBP to phosphorylated CREB. These results suggest that PE stimulates phosphorylation and DNA binding activity of CREB in adult rat ventricular myocytes through multiple signaling pathways involving ERK1/2, p38 MAPK, MSK1 and PKA. The same pathways seem to regulate atrial natriuretic peptide (ANF) mRNA expression, a highly conserved marker gene of cardiac hypertrophy, suggesting that the PE-stimulated activation of CREB is likely to play an important role in the hypertrophic response.

Adrenergic Agonists↗
PubMed2001

Expression of the cAMP response element binding protein (CREB) in hippocampus produces an antidepressant effect.

BACKGROUND: Recent studies have demonstrated that chronic antidepressant treatment increases the expression of the cyclic amp (cAMP) response element binding protein (CREB) in rat hippocampus. The study presented here was conducted to determine if CREB is a relevant target that produces an antidepressant-like effect. METHODS: We employed the herpes simplex virus (HSV)-mediated gene transfer technique to overexpress CREB and determined its effect on the learned helplessness and forced swim tests, two established models used for pharmacological screening of antidepressant drugs. RESULTS: In the learned helplessness model, rats that received bilateral microinjection of HSV-CREB into the dentate gyrus showed significantly fewer escape failures in the subsequent conditioned avoidance test than those injected with control vector (HSV-LacZ). In contrast, microinjection of HSV-CREB in either the CA1 pyramidal cell layer of hippocampus or the prefrontal cortex did not produce an antidepressant response. In the forced swim test, CREB expression in the dentate gyrus resulted in a significantly shorter immobility time than those injected with HSV-LacZ. CONCLUSIONS: These results demonstrate that over-expression of CREB in hippocampus results in an antidepressant effect and suggest that CREB may serve as a potential molecular target for novel therapeutic agents.

Animals↗
PubMed2002

CREB transcriptional activity in neurons is regulated by multiple, calcium-specific phosphorylation events.

The transcription factor CREB mediates diverse responses in the nervous system. It is not known how CREB induces specific patterns of gene expression in response to different extracellular stimuli. We find that Ca(2+) influx into neurons induces CREB phosphorylation at Ser133 and two additional sites, Ser142 and Ser143. While CREB Ser133 phosphorylation is induced by many stimuli, phosphorylation at Ser142 and Ser143 is selectively activated by Ca(2+) influx. The triple phosphorylation of CREB is required for effective Ca(2+) stimulation of CREB-dependent transcription, but the phosphorylation of Ser142 and Ser143, in addition to Ser133, disrupts the interaction of CREB with its cofactor CBP. These results suggest that Ca(2+) influx triggers a specific program of gene expression in neurons by selectively regulating CREB phosphorylation.

Amino Acid Sequence↗
PubMed2006

Subchronic rolipram delivery activates hippocampal CREB and arc, enhances retention and slows down extinction of conditioned fear.

Rolipram, a type IV-specific phosphodiesterase inhibitor, is known to improve memory under various learning tasks. Moreover, Rolipram treatments have been shown to increase expression and phosphorylation of a key factor for hippocampal memory consolidation, the cAMP-dependent response element-binding protein, CREB. However, the exact correlation between hippocampal CREB phosphorylation and memory improvement induced by Rolipram has not yet been determined in a CREB-dependent type of hippocampal-related learning in normogenic, intact rodents. Here, we report that subchronic Rolipram delivery by using osmotic minipumps increased the basal rat hippocampal expression and phosphorylation of CREB, as well as the expression of the cAMP-dependent, memory-related protein, Arc. In parallel, the same treatment improved memory consolidation of conditioned fear. Furthermore, the increase of CREB phosphorylation and Arc expression consequent to the learning experience was enhanced in Rolipram-treated rats, compared to controls. By evaluating the time course of memory extinction over 10 days after the initial learning test, we also observed significant slowing down of the memory extinction rate in Rolipram-treated rats. This effect could be attributed to CREB phosphorylation and memory having been initially higher, as osmotic minipumps stopped to release Rolipram the first day after the initial learning test. Our data define the conditions through which the pharmacological manipulation of hippocampal CREB expression and activation result in memory amelioration in normogenic, intact animals. These results are relevant for the study of molecular correlates of memory, and may also be important in view of the efforts to design new pharmacological treatments, targeting the CREB pathway and leading to enhancement of learning and memory, even in the absence of patent neuropathology.

Animals↗
PubMed2000

cAMP-independent activation of the adenovirus type 12 E2 promoter correlates with the recruitment of CREB-1/ATF-1, E1A(12S), and CBP to the E2-CRE.

Expression of the transcription unit early region 2 (E2) is of crucial importance for adenoviruses because this region encodes proteins essential for viral replication. Here, we demonstrate that the E1A(12S) protein of the oncogenic adenovirus serotype 12 activates the E2 promoter in dependence of the N terminus and the conserved region 1. Activation is mediated through a cAMP-response element that is bound by CREB-1 and ATF-1. Moreover, the Ad12 E2 promoter is inducible by protein kinase A and repressed by either a dominant-negative cAMP-response element-binding protein (CREB) mutant or the highly specific protein kinase A inhibitor protein underscoring the participation of CREB-1/ATF-1 in promoter activation. E1A(12S) binds to CREB-1 and ATF-1 in dependence of the N terminus and CR1 and is recruited to the E2 cAMP-response element through both cellular transcription factors. Most interestingly, point mutations revealed that E1A(12S) domains essential for binding to CREB-1/ATF-1 and for activation of the Ad12 E2 promoter are also essential for binding to the CREB-binding protein. Due to these data and results obtained in DNA-dependent protein-protein interaction assays, we propose a model in which the cAMP-independent activation of the Ad12 E2 promoter is mediated through a ternary complex consisting of CREB-1/ATF-1, E1A(12S), and CREB-binding protein, which assembles on the E2 cAMP-response element.

Activating Transcription Factor 1↗
PubMed2001

Basic fibroblast growth factor-induced activation of novel CREB kinase during the differentiation of immortalized hippocampal cells.

Growth factors bind to their specific receptors on the responsive cell surface and thereby initiate dramatic changes in the proliferation, differentiation, and survival of their target cells. In the present study we have examined the mechanism by which growth factor-induced signals are propagated to the nucleus, leading to the activation of transcription factor, cis-acting cAMP response element (CRE)-binding protein (CREB), in immortalized hippocampal progenitor cells (H19-7). During the differentiation of H19-7 cells by basic fibroblast growth factor (bFGF) a critical regulatory Ser(133) residue of CREB was phosphorylated followed by an increase of CRE-mediated gene transcription. Expression of S133A CREB mutants blocked the differentiation of H19-7 cells by bFGF. Although the kinetics of CREB phosphorylation by EGF was transient, bFGF induced a prolonged pattern of CREB phosphorylation. Interestingly, bFGF-induced CREB phosphorylation and subsequent CRE-mediated gene transcription is not likely to be mediated by any of previously known signaling pathways that lead to phosphorylation of CREB, such as mitogen-activated protein kinases, protein kinase A, protein kinase C, phosphatidylinositol 3-kinase-p70(S6K), calcium/calmodulin dependent protein kinase, and casein kinase 2. By using in vitro in gel kinase assay the presence of a novel 120-kDa bFGF-inducible CREB kinase was identified. These findings identify a new growth factor-activated signaling pathway that regulates gene expression at the CRE.

Animals↗