CREB Function Research Articles

Cellular Mechanisms Underlying the Anxiolytic Effect of Low Doses of Peripheral Δ9-Tetrahydrocannabinol in Rats

We investigated the effect of low doses of intraperitoneal Delta(9)-tetrahydrocannabinol (THC) on anxiety behavior in rats using the elevated plus maze (EPM). An anxiolytic effect was obtained in a range of doses between 0.075 and 1.5 mg/kg, the 0.75 dose being the most effective. Pretreatment with the CB1 receptor antagonist AM251 fully reversed THC's effect, suggesting CB1 receptors were involved. In order to elucidate the neuroanatomical substrates underlying the effect of the maximal effective dose of THC, we investigated cFos expression in anxiety-related brain regions (prefrontal cortex, nucleus accumbens, amygdala, and hippocampus) of rats exposed to the EPM. THC significantly lowered the amount of cFos in prefrontal cortex and amygdala without affecting the other cerebral areas. As there is increasing evidence that CREB function regulates anxiety-like behavior in rats, the second biochemical parameter we measured was phosphorylated CREB in the same brain areas. Rats treated with THC showed a significant increase in CREB activation in the prefrontal cortex and hippocampus. In the prefrontal cortex this increased activation was linked to an increase in ERK activation, whereas in the hippocampus there was a drop in the activity of CAMKII, a kinase with inhibitory effect on CREB activation. All these effects were reversed by AM251 pretreatment, suggesting that stimulation of CB1 receptors is fundamental for triggering the biochemical events. Our results suggest that the stimulation of these receptors in the prefrontal cortex, amygdala, and hippocampus with the subsequent activation of different signaling pathways is the first event underlying the effects of cannabinoids on anxious states.

Multisite phosphorylation of the cAMP response element-binding protein CREB by a diversity of protein kinases

The prevailing view of stimulus-induced activation of the transcription factor cAMP response element-binding protein (CREB) presumes phosphorylation at serine-133. Although, phosphorylation of this residue seems to be necessary, it is not sufficient to trigger CREB-driven transcription, indicating that other phosphoserine-133-independent mechanisms are required for full activation of CREB. One of these additional regulatory mechanisms influencing the transcriptional state of CREB may involve multiple phosphorylation events on other phosphoacceptor sites in the protein. This review focuses on the phosphorylation modifications of CREB by distinct protein kinases and discusses the possible implications for the function of CREB.

Depletion of cAMP-response Element-binding Protein/ATF1 Inhibits Adipogenic Conversion of 3T3-L1 Cells Ectopically Expressing CCAAT/Enhancer-binding Protein (C/EBP) α, C/EBP β, or PPARγ2

The differentiation of preadipocytes to adipocytes is orchestrated by the expression of the "master adipogenic regulators," CCAAT/enhancer-binding protein (C/EBP) beta, peroxisome proliferator-activated receptor gamma (PPARgamma), and C/EBP alpha. In addition, activation of the cAMP-response element-binding protein (CREB) is necessary and sufficient to promote adipogenic conversion and prevent apoptosis of mature adipocytes. In this report we used small interfering RNA to deplete CREB and the closely related factor ATF1 to explore the ability of the master adipogenic regulators to promote adipogenesis in the absence of CREB and probe the function of CREB in late stages of adipogenesis. Loss of CREB/ATF1 blocked adipogenic conversion of 3T3-L1 cells in culture or 3T3-F442A cells implanted into athymic mice. Loss of CREB/ATF1 prevented the expression of PPARgamma, C/EBP alpha, and adiponectin and inhibited the loss of Pref-1. Loss of CREB/ATF1 inhibited adipogenic conversion even in cells ectopically expressing C/EBP alpha, C/EBP beta, or PPARgamma2 individually. CREB/ATF1 depletion did not attenuate lipid accumulation in cells expressing both PPARgamma2 and C/EBP alpha, but adiponectin expression was severely diminished. Conversely ectopic expression of constitutively active CREB overcame the blockade of adipogenesis due to depletion of C/EBP beta but not due to loss of PPARgamma2 or C/EBP alpha. Depletion of CREB/ATF1 did not suppress the expression of C/EBP beta as we had previously observed using dominant negative forms of CREB. Finally results are presented showing that CREB promotes PPARgamma2 gene transcription. The results indicate that CREB and ATF1 play a central role in adipogenesis because expression of individual master adipogenic regulators is unable to compensate for their loss. The data also indicate that CREB not only functions during the initiation of adipogenic conversion but also at later stages.

Analyses of the Inducible Cyclic Adenosine 3′,5′-Monophosphate Early Repressor (ICER) and cAMP Response Element Binding Protein (CREB) in HL60 Cells: New Insight Leukemogenesis?.

The cyclic AMP response-element binding protein (CREB) is a transcription factor that controls genes that regulate cell differentiation, proliferation and survival. CREB protein overexpression has previously been demonstrated in lymphoid and myeloid leukemia. In contrast, it is lower in healthy samples. To understand CREB role in hematopoiesis and leukemogenesis we focused on ICER (Inducible Cyclic Adenosine 3′,5′-monophosphate early repressor). We hypothesize that ICER, CREB endogenous antagonist, deserves a special consideration in CREB function and in the activation of gene expression. ICER directs its specific binding to cAMP response elements (CREs) functioning as a potent repressor of CREB binding and therefore of cAMP-induced transcription. It has been already demonstrated that ICER directly participates in cell fate in other systems. We have previously found that ICER mRNA was at low level at diagnosis of leukemia, whereas it increased in documented remission samples collected during follow up.We constructed an expression vector for ICER and induced its exogenous expression in HL60 cells. We then tested transcription and translation of a series of genes known to have a direct link with the members of the cAMP/CREB pathway by quantitative gene expression analysis and western blot. To determine wheter ICER protein affected identical cellular targets of CREB by repressing CRE containing promoters, we examined luciferase activity when directed by a promoter made up of 4XCREs sequences post ICER transient induction. By chromatin immunoprecipitation assay (ChIP) we looked at specific genes promoters binding, also in permanent ectopic ICER expression system.Results revealed that ICER protein was detected after 24 hours post transfection with sustained induction after 48 hours, whereas CREB mRNA and protein are down regulated. Density Array made up of 96 genes cited in CREB database (http://natural.salk.edu/CREB) for the high predictive value to contain CRE consensus sequence in their promoter revealed a wide genes expression alterations occurring over time post ICER exogenous expression, counteracting CREB transcriptional function. For some genes we confirmed that mRNA down regulation was representative of protein downregulation.We revealed that luciferase activity was strongly reduced by ICER transient induction. Moreover ChIP analyses revealed that CREB binds to the Bcl-2, ICER and CyA1 promoters in HL60 controlling their transcription. This binding was strongly reduced, in particular for Bcl-2, after ICER stable transfection in HL60 confirming its important role in gene expression reduction.Finally, we hypothesize that CREB over expression might up-regulate target genes, affecting cell proliferation and survival at diagnosis of leukaemia. Insufficient ICER expression might fail to counteract these events. These findings represent an important first step in the understanding of the physiological processes linked to the cAMP/CREB/ICER pathway. The future understanding of ICER role in blocking cAMP activation pathway and the finding of a pool of CREB target genes in HL60 may help understanding leukemogenesis.

Survival of DA neurons is independent of CREM upregulation in absence of CREB

cAMP response element binding protein (CREB) and the related factors CREM (cAMP response element modulator) and ATF1 (activation transcription factor 1) are bZIP-domain-containing transcription factors activated through cAMP and other signaling pathways. The disruption of CREB function in developing and mature neurons affects their development and survival when associated with loss of CREM. Since dopaminergic (DA) neurons are affected in several neurological diseases, we generated CREB conditional mutants in DA neurons by using a newly generated transgenic Cre line targeting the dopaminergic system (DATCre). Here we report the generation and analysis of mutant mice lacking CREB in DA neurons (CREB(DATCre) mutants). During adulthood, lack of CREB leads to a partial loss of DA neurons. Since CREM is upregulated in absence of CREB, we have introduced this mutation in a CREM-/- genetic background to assess a compensatory role of CREM. Additional inactivation of CREM does not lead to a more severe phenotype.

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.

Regulation of αA-crystallin via Pax6, c-Maf, CREB and a broad domain of lens-specific chromatin

Pax6 and c-Maf regulate multiple stages of mammalian lens development. Here, we identified novel distal control regions (DCRs) of the alphaA-crystallin gene, a marker of lens fiber cell differentiation induced by FGF-signaling. DCR1 stimulated reporter gene expression in primary lens explants treated with FGF2 linking FGF-signaling with alphaA-crystallin synthesis. A DCR1/alphaA-crystallin promoter (including DCR2) coupled with EGFP virtually recapitulated the expression pattern of alphaA-crystallin in lens epithelium and fibers. In contrast, the DCR3/alphaA/EGFP reporter was expressed only in 'late' lens fibers. Chromatin immunoprecipitations showed binding of Pax6 to DCR1 and the alphaA-crystallin promoter in lens chromatin and demonstrated that high levels of alphaA-crystallin expression correlate with increased binding of c-Maf and CREB to the promoter and of CREB to DCR3, a broad domain of histone H3K9-hyperacetylation extending from DCR1 to DCR3, and increased abundance of chromatin remodeling enzymes Brg1 and Snf2h at the alphaA-crystallin locus. Our data demonstrate a novel mechanism of Pax6, c-Maf and CREB function, through regulation of chromatin-remodeling enzymes, and suggest a multistage model for the activation of alphaA-crystallin during lens differentiation.

Impaired Bidirectional Synaptic Plasticity and Procedural Memory Formation in Striatum-Specific cAMP Response Element-Binding Protein-Deficient Mice

The striatum has a well documented role in procedural learning and memory. However, the synaptic and molecular mechanisms of acquisition and storage of this form of memory remain poorly understood. We examined procedural memory and plasticity in transgenic mice reversibly expressing a dominant-negative cAMP response element-binding protein (CREB) mutant in the dorsal striatum. In these transgenic mice, corticostriatal long-term potentiation and depression are abolished, indicating that CREB function is essential for bidirectional long-term synaptic plasticity in this structure. Importantly, CREB-deficient animals show reversible alterations in several forms of striatum-dependent memory, including footshock avoidance learning and "response" learning in the cross maze. These findings implicate transcriptional regulation by CREB family transcription factors in striatum-dependent information processing and provide the first clear correlation between procedural learning and memory and synaptic plasticity at the corticostriatal synapse.

Nuclear inhibition of CREB‐driven transcription by Rgs13

Regulator of G protein signaling 13 (Rgs13) negatively modulates G-protein-mediated signal transduction in mast cells and B lymphocytes by acting as a GTPase accelerating protein for Gαi and Gαq. Although Rgs13 binds membrane-bound Gα subunits, it has been localized in the nucleus in some cell types. We found previously that Rgs13 expression inhibits cAMP formation and CREB-dependent transcription in response to Gαs-coupled β-adrenergic receptor stimulation although Rgs13 does not interact with Gαs. Here we show that Rgs13 inhibits CREB-mediated transcription induced by a cell permeable cAMP analogue as well as constitutively active CREB, suggesting a unique regulatory action on this signaling pathway at the level of the transcription factor CREB. Moreover, Rgs13 translocates to the nucleus from the cytoplasm in response to PKA phosphorylation of CREB. Rgs13 does not affect CREB phosphorylation but appears to inhibit CREB-driven transcription by interacting with CREB in the nucleus and interfering with CREB binging to DNA. These results reveal a unique function for Rgs13 as a nuclear inhibitor of CREB function.

Signaling Pathways Regulating Gene Expression, Neuroplasticity, and Neurotrophic Mechanisms in the Action of Antidepressants: A Critical Overview

Regulation of gene expression represents a major component in antidepressant drug action. The effect of antidepressant treatments on the function of cAMP-responsive element binding protein (CREB), a transcription factor that regulates expression of several genes involved in neuroplasticity, cell survival, and cognition, has been extensively studied. Although there is general agreement that chronic antidepressants stimulate CREB function, conflicting results suggest that different effects may depend on drug type, drug dosage, and different experimental paradigms. CREB function is activated by a vast array of physiological stimuli, conveyed through a number of signaling pathways acting in concert, but thus far the effects of antidepressants on CREB have been analyzed mostly with regard to the cAMP-protein kinase A pathway. A growing body of data shows that other major pathways, such as the calcium/calmodulin-dependent kinase and the mitogen-activated kinase cascades, are involved in activity-dependent regulation of gene expression and may also be implicated in the mechanism of action of antidepressants. In this article the available evidence is reviewed with an attempt to identify the reasons for experimental discrepancies and possible directions for future research. Particularemphasis is given to the regulation of brain-derived neurotrophic factor (BDNF), a CREB-regulated gene, which has been implicated in both the pathophysiology and pharmacology of mood disorders. The array of different results obtained by various groups is analyzed with an eye on recent advancements in the regulation of BDNF transcription, in an attempt to understand better the mechanisms of drug action and dissect molecular requirements for faster and more efficient antidepressant treatment.

Cocaine exposure at a sublethal concentration downregulates CREB functions in cultured neuroblastoma cells

Previous studies showed that prenatal cocaine in an animal model decreased brain-derived neurotrophic factor (BDNF) activity in offspring's brain. Since BDNF is one of target genes of cAMP response element-binding protein (CREB), this study examined effects of cocaine on CREB activities in a human neuroblastoma (SK-N-AS) cell line. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazodium bromide) assay indicated that cocaine exposure at 5 μM for 24 h had no significant influences on cell viability. However, a 24-h exposure to cocaine at the same concentration significantly decreased the level of phosphorylated CREB, although no significant changes in total CREB proteins were observed. Consistent with reduced CREB phosphorylation, the electrophoretic mobility shift assay showed that exposure to 5 μM of cocaine for 24 h also inhibited CREB binding activity and significantly decreased BDNF mRNA expression. In addition, exposure to 5 μM cocaine for 24 h attenuated the glutamic acid-evoked increase in the intracellular Ca 2+ concentration. Taken together, these findings suggest that cocaine exposure at the sublethal concentration downregulates CREB functions in the cultured SK-N-AS cell line, and that diminished intracellular Ca 2+ responses may be associated in part with cocaine-induced downregulation of CREB activity.

Interference with 3′,5′-Cyclic Adenosine Monophosphate Response Element Binding Protein Stimulates Apoptosis through Aberrant Cell Cycle Progression and Checkpoint Activation

We previously reported that protein kinase A activity is an important determinant of thyroid cell survival. Given the important role of cAMP response element binding protein (CREB) in mediating the transcriptional effects of protein kinase A, we explored whether interference with CREB family members impaired thyroid cell survival. Expression of A-CREB, a dominant-negative CREB mutant that inhibits CREB DNA binding activity, induced apoptosis in rat thyroid cells. A-CREB inhibited CRE-regulated gene expression but failed to alter the expression of bcl-2 family members or of well-characterized inhibitors of apoptosis. To elucidate the mechanism through which impaired CREB function triggered apoptosis, its effects on cell proliferation were examined. Expression of A-CREB inhibited cell number increases, in part due to delayed cell cycle transit. Protracted S-phase progression in A-CREB-expressing cells was sufficient to activate a checkpoint response characterized by Chk-1, histone H2A.X, and p53 phosphorylation. To determine whether cell cycle progression was required for apoptosis, the effects of p27 overexpression were investigated. Overexpression of p27 prevented cell cycle progression, checkpoint activation, and apoptosis in A-CREB-expressing cells. These data reveal a novel mechanism through which interference with CREB abrogates cell survival, through checkpoint activation secondary to cell cycle delay. This study may explain how interference with CREB induces apoptosis in cells where alterations in the expression of pro- and anti-survival genes are not detected.

P.2.d.003 The effects of fluoxetine on the expression and function of CREB in peripheral T lymphocytes of depressed patients

P.2.d.003 The effects of fluoxetine on the expression and function of CREB in peripheral T lymphocytes of depressed patients

Scientists Home In on Link Between Anxiety, Alcohol Use

Scientists Home In on Link Between Anxiety, Alcohol Use

The HIV-1 Tat Protein Enhances Megakaryocytic Commitment of K562 Cells by Facilitating CREB Transcription Factor Coactivation by CBP

The human immunodeficiency virus type 1 (HIV-1) Tat protein regulates transcription factor functions and alters cellular gene expression. Because hematopoietic progenitor cell (HPC) differentiation requires activation of lineage-specific transcription factors, Tat may affect hematopoiesis in HIV-1-infected micro-environments. We have monitored the molecular effects of Tat on megakaryocytic differentiation in the HPC line, K562. Flow cytometry analysis of CD61 indicated that phorbol myristate acetate (PMA) (16 nM) stimulated megakaryocytic commitment of K562 cells was increased (3- to 4-fold) following exposure to Tat (1-100 ng/ml). Activation of the megakaryocytic transcription factor cAMP regulatory element binding protein (CREB) and its coactivation by the CREB binding protein (CBP) was subsequently monitored. CREB phosphorylation and DNA binding were measured by Western immunodetection and electrophoretic mobility shift assays (EMSA), respectively. Within 2 hrs after stimulation, Tat increased both CREB phosphorylation and DNA binding by 7- to 10-fold. Transient cotransfection with CREB reporter and CBP expression plasmids demonstrated that Tat treatment increases (3- to 4-fold) both PMA-stimulated and CBP-mediated transcription via the cAMP regulatory element. Histone acetyl transferase (HAT) activity was increased (8- to 10-fold) in Tat-stimulated cells, which suggested increased chromosomal accessibility of transcription factors. Two-hybrid cotransfection assays using reporter plasmid containing the GAL4 DNA-binding domain and expression plasmid coding for the GAL4-CBP fusion protein, showed that Tat increases (2-fold) CBP-mediated coactivation of CREB. Both reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis showed that Tat treatment increases CBP gene expression (7- to 9-fold) and protein levels (5- to 7-fold) within 6-12 hrs after stimulation. Our findings indicated that Tat treatment increases both CREB function and CREB coactivation by CBP, which may facilitate megakaryocytic commitment of K562 cells. Induction of this molecular signaling by HIV-1 Tat protein may have relevance in understanding the HIV-induced hematologic manifestations and possibly in regulation of viral infectivity parameters in progenitor cell reservoirs.

Role of cAMP Response Element Binding Protein in Cardiovascular Remodeling

The cAMP response element binding protein (CREB) is a ubiquitously expressed nuclear transcription factor that is activated by various extracellular stimuli. CREB is known to regulate the expression of genes important to cell proliferation, differentiation, adaptation, and survival in many cell types. Loss of CREB function by transgenic overexpression of dominant negative CREB or targeted deletion of the CREB gene revealed that CREB is involved in the differentiation of T lymphocytes, production of growth hormone, and the long-term potentiation of neuronal memory. The role of CREB in cardiovascular system is incompletely characterized and several controversies remain. A growing body of recent evidence, however, has suggested that CREB plays an important role in the cardiovascular remodeling process, including inflammation, cell migration, and apoptosis. Thus, CREB may be a possible target for the treatment of cardiovascular diseases such as atherosclerosis, restenosis, and reperfusion injury.

CAMP Response Element-Binding Protein Regulates Differentiation and Survival of Newborn Neurons in the Olfactory Bulb

The transcription factor cAMP response element-binding protein (CREB) is involved in multiple aspects of neuronal development and plasticity. Here, we demonstrate that CREB regulates specific phases of adult neurogenesis in the subventricular zone/olfactory bulb (SVZ/OB) system. Combining immunohistochemistry with bromodeoxyuridine treatments, cell tracer injections, cell transplants, and quantitative analyses, we show that although CREB is expressed by the SVZ neuroblasts throughout the neurogenic process, its phosphorylation is transient and parallels neuronal differentiation, increasing during the late phase of tangential migration and decreasing after dendrite elongation and spine formation. In vitro, inhibition of CREB function impairs morphological differentiation of SVZ-derived neuroblasts. Transgenic mice lacking CREB, in a null CREM genetic background, show reduced survival of newborn neurons in the OB. This finding is further supported by peripheral afferent denervation experiments resulting in downregulation of CREB phosphorylation in neuroblasts, the survival of which appears heavily impaired. Together, these findings provide evidence that CREB regulates differentiation and survival of newborn neurons in the OB.

Deficits in amygdaloid cAMP-responsive element–binding protein signaling play a role in genetic predisposition to anxiety and alcoholism

We investigated the role of cAMP-responsive element-binding protein (CREB) in genetic predisposition to anxiety and alcohol-drinking behaviors using alcohol-preferring (P) and -nonpreferring (NP) rats. The levels of CREB, phosphorylated CREB, and neuropeptide Y (NPY) were innately lower in the central amygdala (CeA) and medial amygdala (MeA), but not in the basolateral amygdala (BLA), of P rats compared with NP rats. P rats displayed higher baseline anxiety-like behaviors and consumed higher amounts of alcohol compared with NP rats. Ethanol injection or voluntary intake reduced the higher anxiety levels in P rats. Ethanol also increased CREB function in the CeA and MeA, but not in the BLA, of P rats. Infusion of the PKA activator Sp-cAMP or NPY into the CeA decreased the alcohol intake and anxiety-like behaviors of P rats. PKA activator infusion also increased CREB function in the CeA of P rats. On the other hand, ethanol injection or voluntary intake did not produce any changes either in anxiety levels or on CREB function in the amygdaloid structures of NP rats. Interestingly, infusion of the PKA inhibitor Rp-cAMP into the CeA provoked anxiety-like behaviors and increased alcohol intake in NP rats. PKA inhibitor decreased CREB function in the CeA of NP rats. These novel results provide the first evidence to our knowledge that decreased CREB function in the CeA may be operative in maintaining the high anxiety and excessive alcohol-drinking behaviors of P rats.

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.

CREB: the unindicted cancer co-conspirator

The transcription factor cAMP response-element binding protein (CREB) participates in a diverse array of cellular processes, including survival, proliferation and glucose metabolism. A new report by Shankar et al. shows that patients with acute myeloid leukemia (AML) have a greater incidence of relapse when intracellular levels of CREB are elevated. By enhancing expression of certain cell-cycle genes, CREB appears to promote growth-factor-independent proliferation and survival of myeloid cells. The results provide new insights into CREB function and suggest potential avenues for therapeutic intervention.