What turns CREB on?

Cellular Signalling 16 (2004) 1211 – 1227 www.elsevier.com/locate/cellsig

Review

What turns CREB on?

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Mona Johannessen, Marit Pedersen Delghandi, Ugo Moens * Department of Biochemistry, Institute of Medical Biology, University of Tromsø, N-9037 Tromsø, Norway Received 20 April 2004; accepted 4 May 2004 Available online 15 June 2004

Abstract The transactivation domain of the cAMP response element-binding protein (CREB) consists of two major domains. The glutamine-rich Q2 domain, which interacts with the general transcription factor TAFII130/135, is sufficient for the recruitment of a functional RNA polymerase II complex and allows basal transcriptional activity. The kinase-inducible domain, however, mediates signal-induced activation of CREB-mediated transcription. It is generally believed that recruitment of the coactivators CREB-binding protein (CBP) and p300 after signal-induced phosphorylation of this domain at serine-133 strongly enhances CREB-dependent transcription. Transcriptional activity of CREB can also be potentiated by phosphoserine-133-independent mechanisms, and not all stimuli that provoke phosphorylation of serine133 stimulate CREB-dependent transcription. This review presents an overview of the diversity of stimuli that induce CREB phosphorylation at Ser-133, focuses on phosphoserine-133-dependent and -independent mechanisms that affect CREB-mediated transcription, and discusses different models that may explain the discrepancy between CREB Ser-133 phosphorylation and activation of CREB-mediated transcription. D 2004 Elsevier Inc. All rights reserved. Keywords: CREB; Serine-133; Phosphorylation; Mammalians; CREB-interacting proteins

1. Introduction Induction of gene expression by the second messenger cyclic adenosine 3V,5V-monophosphate (cAMP) is generally believed to be mediated by binding of the cAMP response element-binding protein (CREB) to a conserved TGACGTCA sequence present in the promoter of many cAMP-responsive genes. CREB was originally shown to become phosphorylated at serine residue 133 (Ser-133) by an activated cAMP-dependent protein kinase (PKA) and phosphorylation of CREB at this residue allows recruitment of the CREB-binding protein CBP or its paralogue p300. The intrinsic histone acetyltransferase activities and the bridging properties with RNA polymerase II via RNA helicase A of the coactivators CBP/p300 contribute to the augmented CREB-mediated transcription. The functions of CREB and the molecular mecha-

$ Supplementary data associated with this article can be found in the on line version, at doi:10.1016/j.cellsig.2004.05.001. * Corresponding author. Tel.: +47-77-64-46-22; fax: +47-77-64-45-22. E-mail address: [email protected] (U. Moens).

0898-6568/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.cellsig.2004.05.001

nisms governing cAMP-induced activation of CREBmediated gene expression have been excellently reviewed elsewhere [1– 5].

2. Regulation of CREB through Ser-133 phosphorylation 2.1. Stimuli that induce phosphorylation of CREB at Ser-133 A stringent genome-wide analysis for CREB binding motifs resulted in 1349 sites in the mouse genome and 1663 hits in the human genome [6]. This vast amount of putative CREB-regulated genes and the enormous functional diversity of the proteins encoded by these genes indicate the important biological role of CREB in many cellular processes. One mode to investigate the involvement of CREB in the regulation of a specific target gene is by examining whether a stimulus, known to activate the expression of this gene, induces phosphorylation of CREB at Ser-133. So far, about 300 different stimuli have been described in the literature that can provoke

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Table 1 Stimuli that can induce phosphorylation of CREB at Ser-133 CREB activation

Protein kinasesa

References

Growth factor signalling EGF Erythropoietin FGF and FGFR GMC-SF Glucose-dependent insulinotropic peptide Hepatocyte growth factor/scatter factor IGF-I/IGF-II Mast/stem-cell growth factor Neuregulin a and h Nonmyocyte-conditioned medium PDGF Serum Thrombin Thrombopoietin Vascular endothelial cell growth factor

Yes NTb Yes Yes Yes NT Yes NT NT NT Yes Yes/Noc Yes Yes Yes

MEK/ERK/Rsk2 + Msk1 + Msk2, PKA, p38, PKC PKA MEK/ERK/Msk1, p38/MK2, Dyrk1, BTK MEK/ERK/Rsk1, PKC PKA

[7,8] [9] [10,11] [12] [13] [14] [15,16] [14] [17,18] [19] [20] [20,21] [22] [23] [24]

Steroid hormone signalling Aldosterone Hydrocortisone Metyrapone Oestrogens Testosterone

NT NT NT Yes NT

Peptide signalling Adrenocorticotropic hormone Angiotensin II Arginine vasopressin Bone morphogenetic protein Calcitonin gene-regulated peptide Human chorionic gonadotropin Endothelin-1 Exendin-4 Follicle-stimulating hormone/PMSG Gastrin Glia maturation factor Glucagon-like peptide 1 Gonadotropin-releasing hormone Growth hormone Growth hormone-releasing hormone h-Heregulin peptide Insulin, proinsulin C-peptide a-Melanocyte-stimulating hormone Oxytocin Peptones PRL-releasing hormone Parathyroid hormone Relaxin Secretin/glucagons family Stromal cell-derived factor 1 Thyroid hormone Thyroid-stimulating hormone Thyrotropin-releasing hormone

NT Yes Yes NT Yes NT NT Yes NT Yes NT Yes NT Yes NT NT Yes Yes NT Yes Yes Yes NT Yes NT NT Yes Yes

Neurosignalling Adenosine receptor Amyloid protein h Antidepressants, suicides, LiCl Apotransferrin Bombesin receptor Bradykinin Cannabinoids

Yes NT Yes NT Yes NT NT

Stimulus

PKA, MEK/ERK, p38/MK3 PKA, MEK/ERK MEK/ERK, PI3K PKA, PKC, MEK/ERK, p38 PKA, MEK/ERK, PKC, p38 MEK/ERK, p38 MEK/ERK p38/Msk1, PKC/Rsk2

PKA, MEK/ERK, PI3K/PKB

PKA, MEK/ERK/Rsk1, p38 PKA PKA PKA PKA, p38/MK2 + MK3 PKC, p38, MEK/ERK/Rsk2 + Rsk3

MEK/ERK, p38

MEK/ERK

MEK/ERK, p38/MK2, PI3K PKA MEK/ERK PKA, CaMK PKB PKA, GSK-3 PKA, MEK/ERK MEK/ERK/Rsk2 PKA

p38, PKA MEK/ERK, p38, PI3K MEK/ERK CaMK PKC, p38, PKA PKC, MEK/ERK, PI3K

[25] [25] [26] [27,28] [29]

[30] [31] [32] [33] [34] [35,36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47,48] [49,50] [51] [52] [53] [54,55] [56] [57,58] [59] [60] [61] [62]

[63] [64] [65,66] [67] [32,68] [69] [70]

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Table 1 (continued) Stimulus

CREB activation

Neurosignalling CART (cocaine- and amphetamine-regulated transcript Cholinergic receptor Dopamine receptor GABAA receptor Ganoderma extract Glutamate receptor activators Huntingtin with expanded poly Q Mg 2 + removal Monosialganglioside Morphine and apomorphine Neural cell adhesion molecule Neuronal agrin Neuropeptide Y Neurotrophins

Yes Yes NT NT Yes/No Yes NT NT NT NT NT Yes Yes

Neurturin NMDA receptor Opioid receptor P2Y receptor Serotonin receptor Substance P Taurine ZNC(C)PR

NT Yes NT Yes NT NT NT NT

Cyclic nucleotide signalling Adrenergic receptors cAMP analogues Forskolin cGMP analogues PDE inhibitors

Protein kinasesa

NT

References

[71] PKC, MEK/ERK, CaMK PKA, MEK/ERK, CaMK, PKC, PKB PKA, MEK/ERK PKA, PKC, MEK/ERK, p38, CaMK, PI3K MEK/ERK/Msk1 MEK/ERK PKA, PKC, MEK/ERK, CaMK MEK/ERK RTK CaMKII PKC, MEK/ERK/Msk1, MEK5/ERK5/Rsk, PI3K, p38/MK2, CaMKIV

[32,72] [73,74] [75] [76] [77,78] [79] [80] [81] [82] [83] [84] [85] [86]

PKC, MEK/ERK

[87] [78] [88] [89] [90] [91] [92] [93]

Yes Yes/No Yes Yes Yes

PKA, PKA, PKA, PKG, PKA

[94] [14,57] [20] [95] [96]

Cytokines IL-1a, IL-1h, IL-2, IL-3, IL-8 Leukemia inhibitory factor TGF-a, TGF-h1 TNFh

Yes Yes Yes Yes/No

PKA, PKC, MEK/ERK, p38/Msk1, RTK MEK/ERK/Rsk2 PKA, PKC p38/Msk1

NO and oxidative stress DETA-NONOate/DETA-PAPA-NONOate Glucoseoxidase H2O2 Na-nitroprusside S-nitroso-N-acetylpenicillame SIN-1 Xanthine and xanthine oxidase YC-1

Yes NT No NT NT NT NT NT

Viral, bacterial, and plant components Actinobacillus actinomycetemcomitans Hsp 60 Brucella suis infection Cholera toxin 3,3V-Diindolylmethane FMLP HBV pX HHV-6 infection HIV Tat protein Luteolin Mitogens (conA, LPS, PHA) Mycobacterium tuberculosis infection

NT NT NT NT NT Yes NT Yes NT Yes NT

PKA, PKC, MEK/ERK, CaMK, PI3K PKA, PKC PKA, PKC, MEK/ERK PKA PKC

MEK/ERK MEK/ERK, p38 PKC, MEK/ERK/Rsk1 + Rsk2, PI3K, RTK MEK/ERK

MEK/ERK, p38, PI3K

PKG/ERK

MEK/ERK/Rsk2, p38 PKA PKA MEK/ERK, p38 MEK/ERK, p38 PKA, MEK/ERK PKA PKA, PKG, MEK/ERK/Msk1 + Msk2, p38, CaMK

[97,98] [99] [77,100] [101]

[102] [103] [27,104] [105] [106] [107] [108] [109]

[110] [111] [112] [113] [114] [115] [116] [117] [118] [33,119,120] [121] (continued on next page)

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Table 1 (continued) Stimulus

CREB activation

Protein kinasesa

References

Viral, bacterial, and plant components Peptidoglycan Pertussis toxin Quercetin Schistosoma manosi excretory/secretory products Staphylococcal enterotoxin A Secalonic acid D Sunghyangjungisan Tetanus Trypanosoma cruzi glycoprotein Yersinia pseudotuberculosis YOP J
mutant

Yes NT NT NT NT NT NT NT NT Yes

Phospholipids/lipidsignalling Arachidonic acid C2 ceramide 12 (S) hydroxyeicosatetraenoic acid OxPAPC Phospholipids Prostanoids Sphingosine 1-phosphate

NT NT Yes Yes NT Yes NT

Immune cell signalling Anti-CD antigens/CD ligands Anti-ICAM-1 Anti-IgG Anti-IgM Anti-MHC class II Cyclosporin A RANTES/TRIAL

No NT NT Yes NT NT Yes

PKA, PKC, MEK/ERK/Rsk2, p38, CaMK PKA, PKC, MEK/ERK PKC PKA, PKC, MEK/ERK, p38/MK2, CaMK PKA

Enviromental stress factors Dark/light cycles Ethanol Fasting/refeeding after starvation Fear Histamine Hypertension Hypoxia and ischemi Irradiation and UV Odor Pain (injury, electric shock, hemorrhage) Stress (hypertonic saline, sorbitol, arsenite) Training and muscle exercise

Yes Yes Yes NT NT NT Yes/No Yes NT NT Yes Yes

CaMK PKA, CaMK PKA PKA, PKC, CaMK, PI3K PKC, MEK/ERK CaMK, PKG PKA, CaMKII MEK/ERK/Msk1 + Msk2, p38/MK2 MEK/ERK PKA MEK/ERK/Msk1, p38/MK2, CaMKIV

[79,146] [147] [148] [127,149] [89] [150] [151,152] [153,154] [155] [156,157] [158,159] [160,161]

Ion channels/intracellular Ca 2 + signalling Ca-ionophores Ca-phosphate dehydrate/basic Ca-phosphate crystal High Ca2 + concentration KATP channel blockers L-type Ca2 + channel activator Membrane depolarization Quabain Ryanodine Thapsigargin

Yes/No NT Yes NT Yes Yes NT NT Yes

MEK/ERK, CaMK

[140,162] [163] [164] [165] [166] [94,167] [168] [169] [170]

Miscellaneous Amphoterin Anisomycin Bile acids TUDCA and TCDCA Calyculin Cycloheximide dsRNA/polyIC DNA akylating agent MNNG

NT NT NT NT NT Yes Yes

PKA PI3K MEK/ERK, p38 p38

[33] [112] [122] [123] [124] [125] [126] [127] [128] [129]

PKC, MEK/ERK, p38 p38 PKA, PKC, MEK/ERK, p38 PKA, MEK/ERK/Msk1, p38 PKA, MEK/ERK CaMK, p38/Msk1, RhoA kinase

[130] [131] [132] [133] [134,135] [136,137] [138]

PKA PKA

MEK/ERK, PI3K/PKB

CaMK PKA, MEK/ERK/Rsk1 + Rsk2, p38, CaMK, PKC, PKG

MEK/ERK MEK/ERK/Msk1 + Msk2, p38

PKA PKA

[139,140] [141] [142] [143] [124] [144] [56,145]

[171] [172] [173] [174] [130] [175] [176]

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Table 1 (continued) Stimulus Miscellaneous Glucosamine Glucose ICER overexpression Insecticides JNK inhibitor SP600125 KIF17 Laminin a-Macroglobulin Mitochondrial activity impairment Pb-acetate TPA Trichostatin A Vitronectin

CREB activation

Protein kinasesa

References

NT Yes NT NT Yes NT NT NT Yes NT Yes/No Yes NT

PKA, PKC

[177] [178] [179] [180] [181] [182] [171] [183] [184] [155] [20,139] [185] [186]

p38

PKA, PKC, MEK/ERK, p38, CaMK, PI3K CaMKIV PKC, MEK/ERK, CaMK PKA, PKC, MEK/ERK/Msk1 + Msk2 + Rsk2, p38/MK2, CaMK

Representative references have been selected. For a complete overview of specific stimuli, cell-type specificity, protein kinases involved, and references, the reader is referred to the extended table provided as supplemental material. a Abbreviations: BTK = Bruton’s tyrosine kinase; MK2 = MAPKAPK2; MK3 = MAPKAPK3; RTK = receptor tyrosine kinase. b NT = not tested. c Whether a stimulus can (yes) or cannot (no) activate CREB-dependent transcription is cell-specific.

CREB phosphorylation. Table 1 summarises the wide variety of stimuli and environmental conditions that provoke phosphorylation of CREB on Ser-133 and their property to activate CREB-mediated transcription in mammalians (a complete list specifying each individual stimulus, as well as the cell or tissues in which the stimuli were tested is available as supplemental material). Inhibitors of CREB phosphatases, like, e.g. okadaic acid, have not been included as they prolong rather than induce CREB phosphorylation. 2.2. Kinases that phosphorylate CREB at Ser-133 The use of specific protein kinase inhibitors soon led to the discovery that PKA is not the sole kinase that can phosphorylate CREB at Ser-133. In fact, this residue turned out to be a in vitro and/or in vivo phosphoacceptor site for several other protein kinases that are enlisted in Table 2. The ability of cGMP-dependent protein kinase (PKG) to phosphorylate CREB both in vitro and in vivo was shown by [95], but was not confirmed by others [105]. In addition to the protein kinases mentioned in Table 2, several other putative CREB kinases have been reported. The human granulocyte-specific kinase CKLiK (calmodulin kinase I-like kinase) is activated by interleukin-8. CKLiK can phosphorylate CREM at Ser-117 in vitro and activates GAL4-CREB directed transcription. Whether CKLiK could phosphorylate CREB was not examined, nor was the effect of the Ser-133 into Ala substitution on GAL4-CREB-dependent transcription when CKLiK was co-expressed tested. However, IL8 induced increased phosphoser-133 CREB levels, suggesting the involvement of CKLiK [198]. Neurotrophin stimulation of rat embryonic dorsal root ganglia increased ERK5 phosphorylation and kinase activity. A dominant-

negative MEK5 inhibited neurotrophin-induced ERK5 phosphorylation and blocked CREB phosphorylation, pointing to a role for ERK5 in CREB phosphorylation [86]. Whether CREB is a bona fide substrate for ERK5 remains to be established. UVC irradiation or EGF treatment of HeLa cells induced the activity of a f 108 kDa protein that could phosphorylate the CREB peptide [153]. The f 100 kDa Msk1 protein kinase probably represents this UV- or EGF-activated CREB kinase [199], although the 105 – 110 kDa ERK5 cannot be excluded [200]. Another group reported that overexpression of wild-type Dyrk3 provoked CREB phosphorylation at Ser-133, and stimulated CREB-dependent transcription. However, kinase inactive Dyrk3 mutants were also able to stimulate the CRE-dependent promoter. Specific PKA inhibitors blocked the ability of Dyrk3 to phosphorylate CREB and to activate CREB-mediated transcription. These results suggest that CREB is not a direct substrate for Dyrk3, but rather that Dyrk3 engages PKA to modulate CRE/CREB regulated transcription [201]. 2.3. Phosphatases that dephosphorylates phosphoserine-133 Several protein phosphatases have been shown to regulate the phosphorylation status of CREB. They act either directly on CREB, or they may govern the phosphorylation status of CREB indirectly by controlling the enzymatic activity of CREB kinases. The serine –threonine protein phosphatase 2A (PP2A) directly dephosphorylates CREB at Ser-133 in hepatocytes, while PP1 is the major CREB phosphatase in NIH 3T3 and PC12 cells [202 – 204]. Hypoxia-induced hyperphosphorylation of CREB in T84 cells coincided with depletion of PP1,

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Table 2 Proven and potential protein kinases that may phoshorylate CREB CREB kinases

Phosphorylation site

References

Bruton’s tyrosine kinase CaMKI CaMKII

Ser-133 Ser-133 Ser-133, Ser-142, Ser-143 Ser-98, Ser-133 Ser-156 Ser-133 Ser-129 Ser-133 Ser-133

[187] [5] [188,189]

CaMKIV Casein kinase II Dyrk1A GSK-30 a and h LIM kinase 1 MAPKAPK RSK1, RSK2, p70SK6, Msk1, Msk2 (RSK-B), MAPKAPK2, MAPKAPK3 PKA PKB/Akt PKC PKG Hypoxia-induced kinase(s) Cell cycle-regulated kinase(s)

[5] [190] [191] [192] [193] [5,194]

Ser-133 Ser-133 Ser-89, Ser-121, Ser-133 Ser-133 Ser-117, Ser-121

[195] [5] [190,196]

Ser-108, Ser-111, Ser-114

[190]

[95] [197]

Genuine or putative in vivo and/or in vitro CREB phosphoacceptor sites for each kinase are shown. See text for details.

suggesting that PP1 can dephosphorylate CREB in these cells. However, Ser-117 and Ser-121, rather that Ser-133 seemed to be the target for hypoxia-induced hyperphosphorylation [197]. In vitro phosphorylation of CREB with CaMKIV occurred predominantly at Ser-133, but also at Ser-98 (reviewed in Ref. [5]). PP1 and PP2A gave similar rates of in vitro dephosphorylation of both phosphoserines, while calcineurin (PP2B) was most active towards phosphoser-133. Calcineurin resides in the nucleus, but its physiological significance for dephosphorylation of CREB has not been explored [205]. In fact, studies in rat hippocampal neurons suggest an indirect role for calcineurin in CREB dephosphorylation, as calcineurin potentiated the activity of PP1, presumably by dephosphorylating the PP1 inhibitor I-1 [206]. Another putative CREB phosphatase is the tumour suppressor PTEN. Ectopic expression of PTEN into PTEN-null prostate cancer cells completely blocked phosphorylation of Akt/PKB, and diminished phosphorylation of CREB in a dose-dependent manner, but had no effect on the total levels of CREB protein [207]. Knowing that Akt/PKB can phosphorylate CREB, it is tempting to speculate that PTEN influences the phosphorylation state of CREB through inhibition of Akt/PKB rather than by direct dephosphorylation [208,209]. Protein tyrosine phosphatase 1B (PTP1B) may represent another phosphatase that indirectly dephosphorylates CREB. Treatment of ob/ob diabetic mice with PTP1B antisense oligonucleotides decreased phosphoCREB levels, but increased levels of the p38- and ERKspecific MAPK phosphatase PAC1 [210]. PAC1-mediated

dephosphorylation of ERK and p38 probably ablates p38and/or ERK-induced activation of the MAPKAPK that can phosphorylate CREB (see Table 2). Animals treated with PTP1B antisense oligonucleotides showed a 20% decrease in PKA activity, which may also have contributed to the decreased phosphoCREB levels [210]. Additional studies in PTP1B
/
mice may shed light on the role of PTP1B in CREB dephosporylation.

3. Other post-translational modifications of CREB Although phosphorylation of Ser-133 is generally accepted to be a key event in the regulation of CREBmediated transcription, several additional modifications can influence the transcriptional activation state of CREB, including other post-translational modifications as discussed below. 3.1. Phosphorylation of CREB at other residues than Ser-133 Additional phosphoacceptor sites for specific CREB kinases are given in Table 2. CREB became phosphorylated at Ser-98 in vitro at relatively high concentrations of PKA. However, mutating this residue into alanine had no effect on GAL4-CREB-mediated transcription, suggesting that phosphorylation at this residue probably was an in vitro artefact and is not biological relevant [211]. Ser-98 is also a target for CaMKIV in vitro, but the physiological significance of this phosphorylated remains unknown (reviewed in Ref. [5]). Phosphopeptide mapping of in vitro PKC phosphorylated CREB revealed two additional phosphopeptides with an unidentified threonine and an unidentified serine as phosphoacceptors. Ser-89 and Ser121 have been suggested as plausible candidates [189,190,212]. Another group detected only dual in vitro phosphorylation of CREB by PKC, but the identity of both sites remains unclear [213]. CaMKII phosphorylates CREB at both Ser-133 and Ser-142 [188,189], while a recent study showed additional phosphorylation of CREB at Ser-143 by CaMKII (see Section 5.3). Phosphorylation of CREB at Ser-133 also creates a consensus site for phosphorylation by glycogen synthase kinase-3h (GSK3h) at Ser-129. Substitution of Ser-129 by Ala strongly impaired forskolin-induced GAL4-CREB-dependent transcription in PC12 cell, but had no effect in NIH3T3 cells [192,214]. GSK-3 may also play a physiological role in parathyroid hormone (PTH) signalling, as PTH-induced stimulation of GAL4-CREB activity depended partially on the phosphorylation of Ser-129 [55]. In contrast to stimuli-induced phosphorylation, Saeki et al. [190] reported a cell cycle-dependent hyperphosphorylation of CREB at the early S-phase in human amnion FL cells. Ser-133 was not a target for cell cycle-induced phosphorylation, but rather Ser-108, Ser-111, and Ser-114. These residues are

M. Johannessen et al. / Cellular Signalling 16 (2004) 1211–1227

located in a region matching the consensus sequence for casein kinase II (CK-II). Replacing both Ser-111 and Ser114 by glutamic residues generated a double mutant with enhanced transcriptional activity compared to wild-type CREB, suggesting that phosphorylation of these sites may increase transcriptional activity. Ser-156 is also a phosphoacceptor for CK-II. The importance of phosphorylation of this residue is not known, but it does not seem to influence Ser-133 induced phosphorylation, as mutation of Ser-156 did not abrogate cAMP-induced CREB activation. CK-II-phosphorylated CREB was readily dephosphorylated by PP2A, but was completely resistant to PP1 treatment [215]. 3.2. Acetylation Acetylation has emerged as an important regulatory mechanism of protein functions, yet the processes that provoke protein acetylation are poorly understood (reviewed in [216]). CBP can acetylate CREB at Lys91, Lys-96, and Lys-136, although to different extent. Sequences surrounding Lys-136 does not fit the CBP consensus acetylation motif, yet Lys-136 had the highest level of acetylation in vitro. Double or triple mutations that replace the lysine residues by alanine or arginine became less acetylated but significantly enhanced CREBmediated transcription both under basal and PKA-activated conditions compared to wild-type CREB. The exact mechanism for acetylation-induced regulation of CREB activity remains unknown, but did not seem to involve DNA or CBP binding, nor did this modification enhance phosphorylation of Ser-133 by PKA. The authors hypothesised that structural changes induced by acetylation may prolong CREB phosphorylation by diminishing phosphatase-dependent attenuation of CREB activity, either by directly interfering with recruitment of phosphatases or by altering phosphatase recognition of CREB as a substrate [217]. This assumption can be tested by monitoring CREB phosphorylation kinetics in forskolin-treated cells transiently transfection with GAL4-CREB or GAL4CREBK91A/96A/136A. The use of GAL4-fusion proteins allows differentiation between endogenous and ectopic expressed CREB. 3.3. Ubiquitination and SUMO-ylation Ubiquitination and SUMO-modification may also regulate of the activity of CREB. Hypoxia treatment of T84 cells led to following temporal events: depletion of PP1 levels, hyperphosphorylation, ubiquitination, proteasomal degradation of CREB, and reduced CREB-dependent transcription. Ser-133 was not likely the phosphoacceptor site because Western blot analyses with antiphosphoserine-specific antibodies of CREB immunoprecipitates from hypoxia-treated T84 cells stably transfected with either wild-type CREB or CREBS133A mutant gave compara-

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ble phosphoserine levels. The CREB sequence DSVTDS between residues 115 and 121 is similar to the phosphorylation-targeted degradation consensus motif DSCXXS (C = large hydrophobic residue, X = any amino acid). This potential proteasomal-targeting motif served as a substrate for PP1 [197]. However, under prolonged hypoxia conditions, a fraction of CREB protein became SUMO-ylated. SUMO-modification stabilised CREB protein and enhanced CREB-dependent reporter gene activity. Three CKXE-like SUMO-modification motifs are present in CREB: EKSE, RKRE, and KKKE (residues 154 – 157, 284– 287, and 303– 306, respectively). Mutating lysine-285 and lysine-304 resulted in decreased SUMO-modification of CREB both in vitro and in vivo. Lysine-304 resides within the nuclear localisation signal of CREB, and substituting this residue by arginine to maintain the nuclear localisation activity but to destroy the SUMO-acceptor site resulted in loss of nuclear localisation of CREB. This observation implicates a role for SUMO-ylation in subcellular localisation of CREB [218]. 3.4. Glycosylation CREB can be covalently modified by O-GlcNAc glycosylation in vivo at two residues within the amino acid residues 256– 261 of the Q2 domain. Putative glycosylation sites are Ser-260 and Thr-256, -259, and -261. Glycosylation impaired the ability of CREB to associate with TAFII130/135 by more than 50%. In vitro transcription studies using HeLa cell nuclear extracts and non-glycosylated or glycosylated CREB revealed that glycosylation inhibited CREB-mediated transcription by 41.5% [219].

4. Regulation of CREB activity through CREB-interacting proteins 4.1. CREB-interacting proteins The CREB protein has a modular structure with distinct domains exerting different functions. The basic leucine zipper motif mediates dimerization and DNA binding, while the glutamine-rich domains Q1 and Q2, and the kinaseinducible domain (KID) constitute the transcription activation domains of CREB. These different domains can recruit distinct proteins that can modify the transcriptional activity of CREB. CREB-interacting proteins and their effect on CREB-dependent transcription are summarised in Table 3. The interaction of the coactivators CBP and p300 with the KID domain of CREB and of hTAFII130/135 with the Q2 domain and their roles in CREB-mediated transcription has been extensively reviewed and will not be discussed here [3 –5]. The different mechanism by which CREB-interacting proteins can affect CREB-mediated transcription will be enlighted in this section.

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Table 3 Proteins that interact directly with CREB and their effect on CREBmediated transcription CREB-interacting protein

Interaction domain on CREB

CREB-mediated transcription

References

v-Abl AP2a Barx2 BRCA1 CIITA CBP, p300 C/EBPh ( = NF-IL6) CREM/ATF members DNA topoisomerase II FHL/ACT HGABPa Gli2h HDAC1 IE86 Jun members LFB3( = vHNF1 = HNFh) Oct1 PX p53 RIIh (PKA) SF1 TAFII130/135 Tax TFIIA Tip60 TORC YY-1 ZPK

Q2 NDa ND bZip ND KID Q1

activation activation ND activation activation activation activation

[220] [221] [222] [223] [224] [3] [162]

bZip

[225]

bZip

activation/ inhibition ND

KID bZip ND Q1 and Q2 ND bZip bZip

activation activation activation inhibition activation activation ND

[227] [228] [229] [185] [230] [231] [232]

ND bZip bZip ND ND Q2 bZip KID + Q1 + Q2 KID + Q2 bZip bZip bZip

activation activation NAb Inhibition Activation Activation Activation Activation Inhibition Activation Inhibition Inhibition

[233] [234] [235] [236] [237] [4] [238] [239] [240] [241,242] [243] [244]

[226]

See text for details. a ND = not determined. b NA = not applicable.

4.2. Mechanisms by which CREB-interacting proteins can regulate CREB-dependent transcription 4.2.1. Increased DNA binding affinity Hepatatis B virus avails itself of CREB to transcribe its viral genes. The viral transactivator protein pX interacts directly with CREB and the pX-CREB complex possesses increased DNA binding affinity, which may enhance CREBmediated transcription [234]. The cellular transcription factor Gli2h also enhances the binding of CREB to DNA thereby potentiating CREB-mediated transcription [229]. 4.2.2. Altered phosphorylation profile of Ser-133 The Ets-related human GA-binding protein a (hGABPa) interacts both with CREB and ATF-1. Binding of hGABPa to ATF-1 resulted in increased phosphorylation of ATF-1, which may enhance the recruitment of CBP. In addition, hGABPa itself binds CBP, thus generating a large transcriptional complex [228]. It was not tested whether hGABPa

induced CREB phosphorylation, but because of the high homology between the KID domains of these two proteins, it seems likely that a similar mechanism is applicable for CREB. CREB can also associate with proteins not directly involved in transcription. For example, the type IIh regulatory subunit of PKA (RIIh) interacts directly with CREB in vitro and in vivo. Overexpression of RIIh inhibited CREdependent promoters and the transcriptional activity of GAL4-CREB, but had no effect on Ser-133 CREB phosphorylation nor on in vitro binding to the c-fos CRE motif. Interestingly, nuclear RIIh levels are abnormally high in T cells of some patients with systemic lupus erythematosus. Binding of RIIh to CREB may therefore disturb normal expression of CREB-regulated genes, thereby contributing to T cell dysfunction in these patients [236]. The mechanism for RIIh-mediated inhibition of CREB-dependent transcription remains unsolved, but nuclear RIIh may reassociate with nuclear catalytic subunits of PKA, thereby modifying the phosphorylation kinetics of CREB. 4.2.3. Recruitment of additional transactivator domain and/ or coactivators Several CREB-interacting proteins are transcription factors with strong transactivator domains, and they may also interact with the coactivators CBP/p300. Such complexes of CREB and another transcription factor with or without CBP/ p300 may potentiate transcription mediated by CREB. A family of tissue-specific LIM-only proteins, referred to as four-and-a-half-LIM domain (FHL) proteins, interact directly with the KID domain of CREB in a phosphoserine-133independent manner [227]. These proteins possess intrinsic transcription activation domains and they readily enhanced GAL4-CREB-, and GAL4-CREBS133A-mediated transcription, and stimulated transcription of CRE-containing promoters [227,245]. The transcription factor C/EBP-h associates through its C-terminal region with the Q1 domain of CREB. Since ATF1 lacks a Q1 domain, it may explain why C/EBP-h stimulated GAL4-CREB, but not GAL4ATF1-mediated transcription. The authors did not test the effect of C/EBP-h on GAL4-CREBS133A-mediated transcription, but because C/EBP-h strongly enhanced GAL4CREB-dependent transcription in serum-starved cells where little or no phosphoser-133 CREB can be detected, it seems unlikely that the effect of C/EBP-h on CREB-mediated transcription requires phosphorylation of serine-133. The authors also showed that potentiation of CREB-mediated transcription by C/EBP-h required the presence of the transactivation domain of C/EBP-h, indicating that enhanced CREB-mediated transcription may result from the recruitment of this additional transactivation domain [162,246]. In addition, C/EBP-h was shown to bind CBP/ p300 at a distinct site from that of CREB [247]. Thus C/ EBP-h may attract CBP to CREB in a serine-133-independent way, thereby creating a stronger CREB:C/EBP-h:CBP transcription complex. The relation between C/EBPh and CREB seems to be symbiotic, offering advantages to both

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proteins. The promoter of C/EBPh gene contains CRE motifs and transcription of the C/EBPh gene can be mediated by CREB and enforced by C/EBPh protein through association with CREB [248]. The binding of Oct-1 to CREB represents another example of recruitment of a transcription factor by CREB. Unphosphorylated, but not phosphoserine-133 CREB, interacts with Oct-1, and overexpression of Oct-1 potentiated both GAL4-CREB- and GAL4-CREBS133A-dependent transcription [233]. Thus both Oct-1 and C/EBPh can be involved in the transcription of genes lacking binding motifs for these proteins, but containing functional CRE motifs. Similarly, CREB may participate in the expression of p53-responsive genes lacking a CRE motif. PhosphoCREB helps p53 in recruiting CBP by forming the bridging protein between DNA-bound p53 and CBP. Through the direct interaction between CREB and p53, phosphoCREB – CBP can be recruited to p53responsive promoters, thus allowing the phosphoCREB – CBP complex to diverse from an activator of CRE-dependent promoters to an activator of p53-responsive genes [235]. The Tax protein of human T-cell leukemia virus type I may also help CREB to usurp CBP. Tax binds CREB, as well as the KIX domain of CBP. Tax will only bind to CREbound CREB when the CRE motif is flanked by GC-rich sequences. The Tax dimer serves as an anchor bound to both the flanking GC-rich motifs and to CREB. In vitro formation of the quaternary DNA –CREB – Tax – CBP complex does not require phosphorylated CREB. It is not yet clear, however, whether such complex in vivo contains phosphoser-133 CREB and whether CREB and Tax bind KIX in a mutually exclusive way (reviewed in Ref. [238]). Finally, CREB was shown by a two-hybrid system in unstimulated HeLa cells to interact with steroidogenic factor 1 (SF-1). The non-phosphorylable CREBS133A mutant displayed only 40% binding affinity compared to wild-type CREB under the same experimental conditions [237]. These results suggest the importance of Ser-133 in CREB:SF-1 interaction. Whether Ser-133 per se or its phosphorylated form enforces the interaction with SF-1 is difficult to conclude because unstimulated HeLa cells were shown to possess high background levels of phosphorylated CREB [129]. It also remains to be established whether CREB and SF-1 interact directly or through a common bridging protein. Since both proteins can bind CBP and p300 and knowing that Ser-133 ! Ala mutation decreased the interaction, it is tempting to speculate that CBP/p300 can be involved. SF-1 may therefore potentiate CREB-mediated transcription by helping to recruit CBP/p300. 4.2.4. Functional replacement of KID The association between the glutamine-rich Q2 domain of CREB and TAFII130/135 seems to be sufficient to recruit a functional RNA polymerase II complex that allows basal transcription activity, while recruitment of CBP/p300 through signal-induced phosphorylation of KID enhances transcriptional elongation and reinititation [4]. The tyrosine

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kinase v-Abl interacts in vivo with Q2 and stimulates CREB-dependent transcription in a Ser-133-independent mode. Probably v-Abl stimulates CREB-directed transcription by phosphorylating the carboxy-terminal domain of RNA polymerase II, a modification that facilitates promoter clearance and transcriptional elongation [220]. According to this model, the v-Abl protein could functionally replace KID thus promoting transcriptional elongation in the absence of CBP and phoshoSer-133. In support of this, co-expression of v-Abl strongly stimulated the low basal transcription activity of a GAL4-Q2 fusion protein [220]. 4.2.5. DNA bending Yin-Yang-1 (YY-1) exemplifies another mechanism by which a CREB-interacting protein regulates the transcriptional activity of CREB. YY-1 was shown to inhibit CREBmediated transcription through bending DNA, resulting in disruption of the physical interaction of CREB with other components of the transcription complex [243]. 4.2.6. Interaction with the general transcription factors A new family of cell- and tissue-specific expressed CREB co-activators, known as transducer of regulated CREB activity (TORC) bind to the bZip domain of CREB. As of today, three members, designated hTORC1, hTORC2, and hTORC3, have been identified. All three TORCs strongly activated CRE-driven transcription and stimulated GAL4-CREB-mediated transcription. The N-terminal region of the TORCs possesses the putative conserved PKA phosphorylation consensus sequence RKXS, while the Cterminal glutamine-rich region contains transcriptional activation potentials. This region interacts with TAFII130/135, and overexpression of TORC enhanced the association of CREB with TAFII130/135. The presence of a conserved PKA phosphorylation site suggests that TORCs and CREB could be coordinately regulated by PKA. The transcriptional potentials of the GAL4-TORC fusion proteins were not monitored in the presence of PKA to confirm this [241,242]. In a recent study, the a-subunit of TFIIA was isolated as an interaction partner for CREMH , CREB, Sp1, but not c-Jun. The association of TFIIA with CREMoˆ was independent of the presence of Ser-117, the homologe of Ser-133 in CREB, but required multiple domains, including the Q1, Q2, and KID domains. Whether TFIIA influence CREB-mediated transcription was not investigated [239]. Interestingly, hTAFII130/135 interacts both with TFIIA and CREB, indicating an intimate relation between these three proteins [249]. The human cytomegalovirus 86 kDa major immediate early protein IE86 ( = IE2) may also modulate CREBdependent transcription by binding to general transcription factors. IE86 interacts directly with CREB and stimulates GAL4-CREB-driven transcription. The precise mechanism by which IE86 stimulates CREB remains elusive, but IE86 interacts with the TATA-binding protein and TFIIB, which may stabilise the RNA polymerase II complex. Moreover, IE86 binds CBP and the CBP-associated factor P/CAF and

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increases the histone acetyltransferase activity of the latter. This combined action of IE86 may increase CREB-mediated transcription [230].

to construct an efficient transcription complex (reviewed in Ref. [5]). 5.2. A nuclear inhibitor prevents the KID:KIX association

4.2.7. Disturbance of the CREB –CBP connection The ubiquitously expressed Tat-interacting protein Tip60 binds directly to CREB. Overexpression of Tip60 reduced basal GAL4-CREB-mediated transcription by 40%, while PKA-induced activation of GAL4-CREB-dependent transcription was inhibited by more than 90%. Tip60 did not inhibit phosphorylation of CREB by PKA in vitro, indicating that the mechanism of Tip60 inhibition involves a step subsequent to phosphorylation of Ser-133, such as preventing binding of CBP to the phosphorylated KID domain, or by inhibiting the activity of the CREB – CBP complex. Tip60 may also interfere with CREBmediated transcription by reducing the initiation processes by the Q2 domain [240].

5. Ser-133 phosphorylation: foreplay or main act? It is generally accepted that phosphorylation of Ser-133 is necessary, but not always sufficient for stimulus-induced activation of CREB. Stimuli like serum, dibutyryl cAMP, TPA, hypoxia, glutamate, TGF-h, and ionophore A23187 induce phosphorylation, but not activation of CREB in some cell types, while they provoke both phosphorylation and activation in other cell types (Table 1 and references in table of supplementary data). Other stimuli can provoke CREB phosphorylation with comparable kinetics and stoichiometry, yet not all stimuli are able to induce CREB-mediated transcription to the same extent (reviewed in Ref. [3]). In 1995, Bonni et al. [250] proposed that: ‘‘In response to each stimulus, an event in addition to CREB Ser133 phosphorylation appears to be required to allow CREB to activate transcription’’. The discrepancy between CREB Ser-133 phosphorylation and CREB activation remains, 15 years after the initial discovery of Ser-133 phosphorylation in vivo by PKA, an unsolved enigma. In other words: what determines whether phosphorylation of Ser-133 is sufficient (‘‘main act’’) or required (‘‘foreplay’’) to turn on CREB? 5.1. Cooperation with other factors is required to mediate phosphoCREB-dependent transcription Nerve growth factor (NGF) induced CREB phosphorylation at Ser-133 and activated transcription of the cAMPresponsive c-fos gene in PC12 cells. However, activation of c-fos transcription in response to NGF required the integrity of the serum response element SRE rather than the CRE, as mutation of this motif, but not the CRE, abolished c-fos induction by NGF. Serum response factor and members of the Elk/Sap family bind to SRE and can associate with CBP. Phosphorylation of CREB may be insufficient to recruit CBP to c-fos, and these other transcription factors may assist

Forskolin and T cell receptor-mediated PKC activation provoked phosphoCREB levels with comparable stoichiometry; however, only forskolin induced CREB –CBP formation and activated CREB-dependent transcription. This indicated that some stimuli, although able to induce Ser133 phosphorylation, failed to subsequently recruit CBP [139]. FRET analysis and studies with specific antibodies recognising the KID:KIX complex confirmed that forskolin, but not TPA, promoted the nuclear interaction of phosphoCREB with CBP. In the cytoplasm, however, CREB – CBP interaction could be detected after forskolin or TPA treatment. To explain the differences in CREB:CBP complex formation in the nuclei of forskolin- or TPA-treated cells, the authors proposed a nuclear inhibitor activity that blocks CREB –CBP complex formation. Some stimuli (e.g. forskolin) may, in addition to inducing phosphorylation of CREB, remove the inhibitory activity, allowing CREB and CBP to associate, while other stimuli (e.g. TPA) cannot abrogate the action of this inhibitor. [251,252]. The identity of this inhibitor and the mechanism that makes the stimulus replace the inhibitor remains unclear. A protein that binds KID and/or KIX could execute this inhibitory activity by preventing interaction between CREB and CBP. Stimulusinduced post-translational modification (e.g. phosphorylation) of the inhibitor may regulate the stability, subcellular localisation, protein – protein affinity, or a combination of these events and thus the ability to prevent KIX – KID interaction. 5.3. Additional phosphorylations of CREB Additional phosphorylation events may control CREBdependent transcription even when Ser-133 is phosphorylated. Indeed, phosphorylation of Ser-142 by CaMKII blocked CaMKIV-induced activation of CREB, and mutation of Ser-142 to alanine enhanced the ability of Ca2 + influx to activate CREB [253]. In agreement with this, Wu and McMurray[189] showed that CaMKII phosphorylated CREB at both Ser-133 and Ser-142, but that phosphorylation of Ser-142 prevented CBP recruitment because this modification disrupts the interaction with Tyr-650 in CBP which is crucial for the KID:KIX interaction. Moreover, phosphorylation of Ser-142 inhibited CREB dimerization of CREB and caused DNA bound CREB to dissociate [254]. On the other hand, Gau et al. [255] found a positive role for Ser-142 phosphorylation in the molecular mechanism that synchronises the circadian clock. Studies with homozygous CREB Ser142 ! Ala mutant mice showed that these mice were impaired in resetting the central circadian clock, and light-induced expression of the CREB-responsive genes c-fos and mPer1 in the supra-

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chiasmatic nucleus was attenuated compared to wild-type mice. Kornhauser et al. [256] found that K+-depolarisationinduced Ca2 + entry not only caused Ser-133 phosphorylation, but also phosphorylation of Ser-142 and Ser-143. Phosphorylation of Ser-142 and Ser-143 developed more slowly than Ser-133, and decayed more rapidly. Mutation of Ser-142 and Ser-143 into alanine reduced Ca2 +-induced CREB-driven transcription, indicating that phosphorylation of these two sites contributes to CREB activation. Ca2 +induced CREB activation via phosphoser-142/phosphoser143 may represent a CBP-independent pathway because the GAL4-CREBS133A mutant could still mediate transcription, although reduced compared to wild-type CREB, in response to KCl. Ser-129 forms a phosphoacceptor site for GSK-3h, and phosphorylation of this site can influence the transcriptional potentials of CREB (see 3.1.). The exact mechanism by which phosphoser-129 modulates CREBdependent transcription remains elusive, as GSK-3h was shown to negatively regulate the DNA-binding activity of CREB [257], while another study revealed that phosphorylation of Ser-129 by GSK-3h subsequent to Ser-133 phosphorylation increased nuclear distribution of this double phosphorylated CREB variant. Interestingly, levels of phosphoser-129/phosphoser-133 CREB were high in low grade (low GSK-3h activity) prostate cancer, but reduced in high grade (decreased GSK-3h activity) prostate cancer tissues [258]. Furthermore, Ser-129 phosphorylation seemed to be required for EGF-induced CREB activation was suggested in UMR 106-01 cells. Mutation analysis showed that both Ser-129 and Ser-133 were required for EFG-induced transcriptional activation of CREB [8]. 5.4. Stimulus-induced activation of CREB-dependent transcription requires the concerted action of multiple kinases The adenylate cyclase activator forskolin is generally applied as an inducer of PKA. However, forskolin has been demonstrated to activate also the MAP kinase MEK1/2 – ERK1/2, p38, and MEK5 –ERK5 modules, and the PI3K – PKB pathway ([254,259 – 261], references in Table 1). Inhibitors of these pathways reduced forskolin-induced CRE-dependent CREB transcription, but not phosphorylation ([20,127,172,262 – 264], Table 1). Similarly, the MEK1/ 2 inhibitor U0126 attenuated PACAP-induced CRE-dependent transcription, but had no effect on CREB phosphorylation [265]. These findings suggest that activation of multiple protein kinases may be required for full activation of CREB, but not for phosphorylation of Ser-133. Thus one plausible explanation for the discrepancy between Ser-133 phosphorylation and CREB activation is the potential of a stimulus to activate only one or several CREB kinases that in addition to Ser-133, phosphorylate additional residues in CREB and/or other proteins involved in CREB-mediated transcription.

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5.5. Duration of CREB phosphorylation determines the transcriptional activity of CREB The kinetics of CREB phosphorylation may be of crucial importance for activation of CREB-dependent transcription as transient increase in CREB phosphorylation may be insufficient to stimulate CREB-dependent transcription. For example, signalling through the CaMKIV pathway generated a fast, but transient phosphorylation of CREB, while a more slowly, but prolonged phosphorylation profile is maintained through the MEK/ERK pathway [266,267]. Stimuli that engage both pathways may activate CREB, while stimuli that signal through only one of these pathways may fail to do so. The difference between EGF and bFGF to stimulate CREB-dependent gene expression in immortalized hippocampal progenitor H19-7 cells can also be explained by the duration of CREB phosphorylation. EGF generated transient phosphorylation of CREB and was a poor inducer of CREB-mediated transcription, while prolonged phosphorylation and robust CREB-dependent transcriptional response was observed with bFGF [187,191,193]. Another example is H2O2, which induced transient phosphorylation of CREB in human keratinocytes, with increased phosphoCREB levels returning to basal levels already after less than 15 min, while estradiolinduced phosphoCREB levels remained elevated for 5 h. Accordingly, estradiol, but not H2O2, activated a CREdriven promoter [27]. However, duration of the CREB phosphorylation to explain activation of CREB is not operational for TPA in NIH3T3 cells. TPA treatment resulted in CREB phosphorylation with comparable kinetics and stoichiometry as forskolin, but only forskolin was able to vividly induce CREB-mediated transcription [20]. 5.6. Phosphorylations of general transcription factors and coactivators may influence the outcome of phosphoCREBmediated transcription CREB-mediated transcription may, in addition to Ser133 phosphorylation, require post-translational modification of components of the RNA polymerase II transcription complex. We found that the intrinsic transcriptional activity of TAFII130/135 was enhanced by forskolin, but not TPA in NIH3T3 cells (our unpublished results), while specific inhibition of PP2A by SV40 small t-antigen enhanced transcription by the GAL4-TAFII130/135, indicating post-translational modifications of TAFII130/135 [268]. Post-translational modification of TAFII130/135 may stimulate transcription initiation, and could explain the different abilities between TPA and forskolin to stimulate CREB-conducted transcription. Also, the activity of coactivators for CREB-mediated transcription can be modulated by phosphorylation. For instance, CBP/p300 recruited by phosphoser-133 CREB may need additional phosphorylation in order to positively or negatively modulate CREB-mediated transcription. In fact, a recent study

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showed that NMDA-induced phosphorylation of Ser-133, but activation of CREB-dependent gene expression required phosphorylation of CBP at Ser-301 by CaMKIV [269]. Stimuli that provoke both CREB and CBP/p300 phosphorylation may hence activate CREB-mediated transcription, while stimuli that fail to induce CBP/p300 phosphorylation are poor activators of CREB-dependent transcription. In addition to CaMKIV, PKA and MAP kinases have been shown to phosphorylate CBP/p300, but controversy exists in the literature whether phosphorylation of CBP and p300 is responsible for stimulusinduced activation of transcription [247]. 5.7. A role for chromatin remodelling factors in stimulusinduced CREB-mediated transcription Distinct histone modifications, such as acetylation and methylation, form an important link between signalling pathways and regulation of gene expression. A striking example is EGF-induced histone H3 phosphorylation at Ser-10 by Rsk-2. This modification accelerates acetylation of Lys-14 on H3, and coincides with transcriptional activation of the CRE-dependent c-fos promoter [270]. Forskolin, a strong inducer of CREB-dependent transcription, enhanced histone H4 acetylation over the CREresponsive somatostatin promoter twofold [271]. This finding underscores the assumption that stimuli that induce chromatin remodelling may facilitate CREB-dependent transcription. Work by two independent groups further illustrates the importance of chromatin remodelling on stimulus-induced expression of CREB target genes. Fass et al. [272] found that the HDAC inhibitor trichostatin A (TSA) enhanced forskolin-induced transcription of the cfos and NUR77 ( = NR4A2) genes, while an inhibition was measured on the NOR-1 and ICER genes. The authors showed that TSA alone blocked formation of the preinitiation complex to the ICER promoter, while TSA induced binding of RNA polymerase II and TFIIB to the NUR77 promoter, and enhanced binding of RNA polymerase II to the c-fos promoter. Canettieri et al. [185] showed that forskolin treatment increased histone H4 acetylation, and displaced HDAC1 from the promoters of the CREB target genes NUR77 and human chorionic gonadotropin-a, resulting in activation of the promoter. CREB interacted directly with HDAC1, which itself is associated with PP1. PP1 – HDAC1 complex promoted dephosphorylation of CREB, thereby attenuating forskolin-dependent activation of CREB-mediated transcription. In such a scenario, it can be imagined that stimuli that cannot activate CREB-mediated transcription fail to supplant HDAC1 from the promoter. Alternatively, stimuli may influence the activity or integrity of the HDAC1 – PP1 complex, thereby affecting CREB-driven transcription. Stimuli may also control the availability of CBP for phosphoCREB. In quiescent cells, CBP can be found in complex with Rsk-2, as well as Rsk1, Rsk-3, and Msk-1. This association inhibited both the

kinase activity of Rsk-2 and the HAT activity of CBP. This enzymatic inactive complex prevented phosphorylation of the Rsk-2 substrate CREB and acetylation of CBP substrate histone H3 [273]. Thus stimuli that can induce disruption of this complex may activate CREB-mediated transcription, while stimuli that fail to provoke dissociation of the complex will not activate CREB although they may permit CREB phosphorylation through other CREB kinases than Rsk2. This mechanism may not be applicable for all stimuli as exemplified by TPA. TPA efficiently induced disruption of the CBP-Rsk-2 in COS cells [273], but is a poor inducer of CREB-mediated transcription in e.g. NIH3T3 cells [20]. While CBP –Rsk-2 complexes can be detected in the latter cells, it was not tested whether TPA induced dissociation of the complex [273]. 6. Conclusions and further challenges Almost 20 years have elapsed since CREB was isolated, the major molecular mechanisms of CREB-mediated transcription were solved, and many of the biological functions of CREB were identified. Despite intensive research, reflected in the more than 4000 articles on CREB published in PubMed, researches are left with a crucial unanswered question: how to explain the discrepancy between CREB phosphorylation at Ser-133 and activation of CREB-mediated transcription? Solving this enigma forms a true challenge for future research. Multiple modifications of CREB as well as its co-activators executed in a timely correct mode may be required to achieve optimal CREB-dependent gene expression in response to signals. The involvement of supplementary phosphorylation events besides Ser-133 phosphorylation urges to re-investigate the phosphorylation pattern of CREB under different conditions. The availability of specific antibodies directed against the additional phosphoacceptor sites will facilitate this task. References Due to space limitations, a selection of references had to be made. We apologize to those authors whose work has not been referred. A complete overview based on English articles available on PubMed of CREB phosphorylation-inducing stimuli, assays, cell type or tissue investigated, and references are provided as supplementary material.

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