Cholecystokinin gene transcription: promoter elements, transcription factors and signaling pathways

Peptides 22 (2001) 1201–1211

Review

Cholecystokinin gene transcription: promoter elements, transcription factors and signaling pathways Thomas v. O. Hansen* Department of Clinical Biochemistry, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark Received 16 November 2000; accepted 22 December 2000

Abstract Cholecystokinin (CCK) is a neuropeptide expressed in the small intestine and in the central and peripheral nervous system. CCK gene expression is both spatially and temporally regulated. In neurons CCK production is increased by growth factors, cyclic adenosine 3⬘, 5⬘-monophosphate (cAMP), dopamine, estrogen, and injury situations, while intestinal CCK expression is mainly regulated by food intake. The function of the proximal CCK promoter has been examined by transfection of human CCK-CAT reporter constructs in cultured cells, DNase I footprinting and gel shift assays. These studies have led to the identification of regulatory elements and transcription factors important for basal and stimulated gene expression and depicted the signaling pathways involved in growth factor and cAMP induced CCK transcription. The review outlines the current knowledge of the regulation of CCK transcription and describes the role of putative transcription factors in tissue-specific CCK gene expression. © 2001 Elsevier Science Inc. All rights reserved. Keywords: Cholecystokinin; Promoter region; Regulatory elements; Transcription factors; CREB; Growth factors; cAMP; Signaling pathways; MAPK; PKA; Tissue-specific expression

1. Introduction Cholecystokinin (CCK) is a neuropeptide expressed in the endocrine I-cells of the small intestinal mucosa and in widespread central and peripheral neurons [95]. Whereas intestinal CCK regulates the release of pancreatic enzymes and contraction of the gall bladder, neuronal CCK is a transmitter assumed to be involved in a variety of central nervous system (CNS) functions such as feeding behavior, anxiety, analgesia, and memory [20]. CCK expression is both tissue-specific and developmentally regulated. In mouse and rat, intestinal CCK levels are high before birth [70,97,131] where CCK-producing endocrine cells are found at embryonic day 15.5 [63]. The expression pattern is biphasic, declining toward birth followed by an increase, which continues into adult life [70]. In mouse and rat brain, CCK levels are low before birth, but increase steadily postnataly during neuronal maturation until adulthood [23,33,43,74,124]. CCK is among the most abundant neuropeptides in the adult brain [19,96] and par* Corresponding author. Tel.: ⫹45-35-45-22-23; fax: ⫹45-35-45-4640. E-mail address: [email protected] (T.v.O. Hansen).

ticularly high levels are expressed in the cerebral cortex, thalamus, and hippocampus, although significant quantities occur in almost any region of the brain [6,23,61,109]. CCK is also widely expressed in peripheral neurons, primarily in the intestinal tract [61], where CCK-producing neurons can be found in the intestine as early as embryonic day 10.5 [63]. Low-level expression has moreover been found in the pituitary corticotrophs [94,99], in thyroid C cells [98], in the adrenal medulla [4], in the bronchial mucosa [35], and in spermatogenic cells [90,91]. Previous studies have shown that CCK expression is regulated at multiple levels. The post-translational processing of proCCK is well established [100], and translational control has also been reported [128]. The primary control of CCK expression is, however, exerted at the level of transcription. The stimuli that control CCK transcription are largely unknown, but in neuronal cells CCK mRNA has been reported to be induced by growth factors [21,82], cyclic adenosine 3⬘, 5⬘-monophosphate (cAMP) [75], dopamine [30], estrogen [46,116], and injury situations [10,38, 139]. In the intestine CCK gene expression is mainly regulated by food intake, but glucocorticoids and pituitary adenylate cyclase-activating polypeptide (PACAP) are also implicated in intestinal CCK expression [17,26,67,92].

0196-9781/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved. PII: S 0 1 9 6 - 9 7 8 1 ( 0 1 ) 0 0 4 4 3 - 0

1202

T.v.O. Hansen / Peptides 22 (2001) 1201–1211

This review describes the current knowledge of the regulation of the CCK promoter, its regulatory elements, transcription factors, and the signaling pathways involved in induction of CCK gene expression. Finally, the role of putative transcription factors in tissue-specific CCK gene expression is discussed.

2. Transcriptional regulation Transcription is regulated by the promoter region located just upstream of the transcriptional start site. The promoter region contains sequence elements that bind specific transcription factors and these sequence elements can be divided into: (a) the core promoter located at or near the transcription initiation site, which interacts with RNA polymerase II and associated factors, comprising the general transcription factor machinery, and (b) gene-specific regulatory elements usually located distal to the core promoter elements, which interacts with gene-specific transcription factors, that modulate the function of the general transcription factor machinery [103]. A typical core promoter encompasses DNA sequences between approximately -40 and ⫹40 nucleotides relative to the transcription start site [7]. Usually, the core promoter consists of a TATA-box, located near position -30 to -25 [9], an initiator element (Inr), located at or near the transcription start site [118], and a TFIIB recognition element (BRE), located just upstream of the TATA-box [59]. In TATA-less promoters a downstream core promoter element (DPE), may moreover be located approximately 30 base pairs (bp) downstream the initiation site [11]. The core promoter determines the start site of transcription, controls the direction of transcription and directs the assembly of the preinitiation complex (PIC). The PIC is comprised of two groups of factors: (a) General transcription factors including RNA polymerase II, TFIIA, TFIIB, TFIID, TFIIE, TFIIF, and TFIIH [104], and (b) co-activators and co-repressors that mediates responses to regulatory signals [79]. The TFIID complex, consisting of the TATA-box binding protein (TBP) and 10 or more TBPassociated factors (TAFIIs) [12] and TFIIB are the only general transcription factors that directly interact with the core promoter. The gene-specific regulatory elements present from about -40 to -200 bp upstream of the transcription start site and the core promoter is commonly referred to as the promoter region, while enhancers/silencers are control regions found at a greater distance from the transcription start site, either upstream or downstream of the gene. Both regulatory elements and enhancers/silencers are recognition sites for sequence-specific DNA-binding transcription factors, which are either cell or tissue-specific and regulate a specific subset of genes, or are present in many cells and involved in the expression of housekeeping genes. These factors typically contain two functional domains: a DNA-binding domain and a transcriptional activation domain that is required

Fig. 1. Structure of the human CCK gene and sequence of the proximal promoter region. Exons are shown by boxes (adapted from [122]). The enlargement shows the sequence of 200 nucleotides from the proximal promoter region and 49 nucleotides of exon 1. The transcriptional start site is indicated by 1. The E-box element, CRE/TRE, and GC-rich region are boxed and the putative TATA-box is underlined.

for transcriptional stimulation [126]. The DNA-binding domain targets the transcription factors to a specific site, while the activator domain interacts with the general transcription factor machinery to either recruit it to the promoter, altering the conformation of this machinery, or by affecting steps after initiation and thereby increasing the transcriptional activity of a specific gene.

3. Regulatory elements in the proximal promoter region of CCK The CCK gene has been cloned and characterized in various species, including man [122,123], rat [27,28], and mouse [33]. The human CCK gene is a single copy gene located on chromosome 3 in the 3q12–3pter region [122]. The gene spans 7 kb and contains three exons that are interrupted by two introns of 1.1 kb and 5 kb, respectively (Fig. 1), and generates a 0.8 kb mRNA. The first exon encodes the 5⬘- UTR of the transcript, while the translation start site (AUG) is present in exon 2. The proximal part of the CCK promoter has been cloned from man [122], rat [33], mouse [131], bullfrog [106] and dogfish [48]. All core promoter regions contain a putative TATA-box element 25– 44 bp upstream of the transcription start site. Only the bullfrog core promoter contains a consensus TATAA box element, whereas the human, mouse, rat and dogfish core promoters contain an atypical TATTT element, whose functional significance remains to be determined. Just upstream of the putative TATA-box, the core promoters contain a GC-rich region that resembles a TFIIB recognition element, which have the consensus sequence G G G /C /C /ACGCC [59]. In contrast, there is no apparent downstream core promoter element (A/GGA/TCGTG) in any of the core promoters. All initiator elements are pyrimidine rich, however, they all differ from the consensus sequence

T.v.O. Hansen / Peptides 22 (2001) 1201–1211

1203

activity of the CCK promoter [85], suggesting that these elements are involved in basal CCK gene expression. In contrast, a point mutation of the GC-rich region, which has been suggested to be associated with alcoholism and panic disorders [42,88,135], had no effect on CCK gene expression [40].

4. Transcription factors involved in activation of CCK gene expression

Fig. 2. Comparison of the proximal promoter regions of the human [122], rat [27], mouse [131] and bullfrog [106] CCK genes. The sequence for the E-box, CRE/TRE, GC-rich region, and TATA-box are boxed, while the transcriptional initiation site is indicated with bold letters.

PyPyA⫹1NT/APyPy with 2 to 3 nucleotides. Transcriptional initiation of human CCK has been reported to occur either 25 or 34 bp downstream the putative TATA-box motif in neuroblastoma cells and in intestinal cells, respectively [85,122]. The CCK promoter region has been characterized via deletion and mutational analysis in transiently transfected cells [44,85]. In this way positive regulatory elements were identified between, or just besides, the nucleotide positions -100 to -92, -84 to -74, and -58 to -37, relative to the transcription start site in the human promoter, while the region between, or just besides, the -102 and -81 in the rat promoter has been reported to contain elements important for transcriptional activity. Sequence analysis of the human promoter showed that the -97 to -92 region contained an E-box element (CACGTG), the -79 to -73 region encompassed a combined cAMP response element (CRE)/12-Otetradecanoylphorbol-13-acetate (TPA) response element (TRE) (CTGCGTCAGC), while the -39 to -32 region contained a GC-rich region (GGGCGGG). The E-box element, CRE/TRE and GC-rich region in the human CCK promoter are conserved in the mouse, rat, and bullfrog promoters (Fig. 2), suggesting that these elements could be important for regulation of CCK gene expression. The dogfish promoter, however, only contains a putative CRE/TRE and a GC-rich region [105]. Therefore it could be argued that the appearance of an E-box element in CCK genes from higher vertebrates has played a role in the evolution of cell specific expression of CCK. In contrast, a recently identified AP-2/NF-kappaB responsive element in the rat promoter [50] is not conserved in the promoters from man, rat, mouse, bullfrog or dogfish. The functional significance of the three elements in CCK transcription was furthermore examined by mutational analysis. Mutation of the E-box or the CRE/TRE reduced the

Transcription factors involved in CCK gene expression have been characterized by conventional DNase I footprint, mobility-shift DNA-binding and supershift assays. Footprint analysis suggested the putative binding of factors to the E-box element, the CRE/TRE and the GC-rich region [85]. Subsequently, mobility-shift DNA-binding and supershift assays using specific antibodies were used to identify transcription factors associated with the particular elements and the functional role of the identified transcription factors were examined by co-transfection studies in different celllines. 4.1. E-box (-97 to -92) element E-box elements (CANNTG) are frequently encountered in promoters and enhancers that regulate muscle-, neuron-, pancreas-, and intestine-specific gene expression [71,78]. The element is recognized by the basic-helix-loop-helix (bHLH) family of transcription factors, that contain a group of positively charged amino acids, the basic region, which is involved in DNA-binding and the HLH motif, which is involved in homo- and heterodimerization with other HLH proteins. The palindromic CACGTG element in the CCK promoter is a consensus recognition sequence for the transcription factors USF1, USF2, c-Myc and Max [69,108, 117]. These transcription factors are ubiquitously expressed and contain a leucine zipper domain adjacent to their bHLH region. They normally bind as USF1/USF2 and c-Myc/Max heterodimers to the E-box element and are involved in transcriptional activation [56,130]. In human neuroblastoma cells USF1 is the major factor that binds the E-box element, and studies showed that USF1 is able to stimulate CCK gene expression [85,105]. However, c-Myc and Max may associate with the E-box element in another cellular context, and co-transfection studies have shown that c-Myc/Max also is able to stimulate CCK transcription [105]. In both cases mutation of the E-box element reduced the stimulatory effects, indicating that the activation is mediated via the E-box element. Previously, it has been demonstrated that Max homodimers can repress transcription by interfering with the binding of USF1/USF2 and c-Myc/Max heterodimers [56]. In this way the E-box element in the CCK promoter may be important in both stimulation and repression of CCK transcription. Moreover, the E-box element has been suggested to be involved in negative regulation of the

1204

T.v.O. Hansen / Peptides 22 (2001) 1201–1211

CRE/TRE, since mutation of the E-box element increased c-Jun/c-Fos mediated CCK gene expression [105]. 4.2. CRE/TRE (-79 to -73) The combined CRE/TRE sequence in the CCK promoter is identical to the TRE(-296) of the c-fos gene and the CRE-2 of the proenkephalin gene [15,16,110]. It consists of a TGCGTCA core that resembles both the 8-bp palindromic CRE sequence (TGACGTCA) and the TRE sequence (TGACTCA), which are found in numerous genes [1,76]. The CRE and TRE sequences are recognized by the basic leucine zipper (bZIP) family of transcription factors, that are characterized by a 30 amino acid region rich in basic amino acids followed by a 30 – 40-residue sequence rich in leucine residues, called the leucine zipper [129]. The leucine zipper mediates dimerization and juxtaposes the two basic regions to form the DNA-binding domain. The bZip transcription factors includes the CREB/ATF family (CREB, ATF-1, CREM) and the AP-1 family (c-Jun, JunB, JunD, c-Fos, FosB, Fra1, Fra2), which are able to form various homo- or heterodimers [1,76]. While the AP-1 proteins are able to bind CREs with only slightly lower affinity than TREs [107], the CREB/ATF proteins tend to have a strong preference for CREs [53]. Since the CRE/TRE in the CCK promoter exhibit a C residue (TGCGTCA) in the core of the element, and therefore resembles a CRE sequence [54,76], it is a potential target by both CREB/ATF and AP-1 transcription factors. In agreement with this CREB and ATF-1 were shown to be the main binding proteins associated with the CRE/TRE using nuclear extracts from SK-N-MC [41, 85]. Similar results are observed using nuclear extracts from PC12 cells (T. v. O. Hansen, unpublished results) and in studies of the rat CCK CRE/TRE using nuclear extracts from the enteroendocrine cell-line STC-1 [26]. However, in vitro transcribed/translated c-Jun and c-Fos proteins are also able to bind the human CRE/TRE (T. v. O. Hansen, unpublished results), raising the possibility that c-Jun and c-Fos could be the predominant binding proteins to the CRE/TRE in other cells or tissues. The functional role of CREB, ATF-1, c-Jun, and c-Fos were examined by co-transfection studies in different celllines. While CREB expression increased CCK promoter activity in F9 cells, expression of ATF-1 had no significant effect on CCK gene expression in these cells [41]. Moreover, ATF-1 reduced basal CCK gene expression levels in SK-N-MC cells, suggesting that CREB is involved in activation, while ATF-1 is involved in repression of CCK transcription. Expression of either c-Jun or c-Fos in SKN-MC cells increased CCK transcription and co-expression was associated with potent synergistic activation [85,105]. The activation potential of c-Jun/c-Fos was almost completely reduced after mutation of the CRE/TRE, showing that the CRE/TRE is responsible for c-Jun/c-Fos induced stimulation. These studies show that CREB and c-Jun/c-Fos bind the

combined CRE/TRE and activates CCK transcription. Since both CREB and c-Jun/c-Fos are induced and activated by several signaling transduction pathways, they are putative mediators of extracellular signals that stimulate CCK transcription (see section 5). 4.3. GC-rich (-39 to –32) region GC-rich regions are present in a wide variety of promoters and are required for appropriate expression of both ubiquitous and tissue-specific gene expression. The GC-rich region in the CCK promoter is a consensus recognition sequence for the Sp family of transcription factors. The ubiquitously expressed member of this family, Sp1, binds GC-rich elements via an 81 residue DNAbinding domain, containing three C2H2-type (Kru¨ppel) zinc fingers, and is involved in transcriptional activation [18]. Recently, other Sp1-related transcription factors were shown to bind and act through the same elements, including Sp3, which was shown to be involved in both repression and activation of genes depending on the promoter and the cellular context [120]. Although DNAbinding analysis has indicated that the GC-rich region in the CCK promoter is able to bind both Sp1 and Sp3 [40,85], the physiological relevance of these factors is unclear. Expression of Sp1 and Sp3 induced only very weak activation of a CCK reporter plasmid, containing 100 bp promoter upstream of the transcription start site [40], indicating that there are no functional Sp1 and Sp3 binding elements in this region. The GC-rich element in the human CCK promoter is located just upstream of the putative TATA-box. Previous footprint experiments have suggested that binding of the general transcription factor complex to the TATA-box protects 10 –20 nucleotides upstream of the TATA-box [80,108,127]. Therefore, the Sp- family of transcription factors are unlikely to bind the GC-rich region simultaneously with the general transcription factor machinery, suggesting that the GC-rich region could be a recognition sequence for TFIIB, and not for Sp1 and Sp3.

5. Signaling pathways involved in CCK transcription In neuronal cells, CCK mRNA levels are induced by growth factors [21,82], cAMP [75], dopamine [30], estrogen [46,116], and injury situations [10,38,139]. Whereas the transcription factors involved in dopamine, estrogene and injury stimulated CCK gene expression is currently unknown, the signaling pathways, transcription factors and regulatory elements involved in cAMP and fibroblast growth factor-2 (FGF-2) induced CCK gene expression have been examined in detail [41].

T.v.O. Hansen / Peptides 22 (2001) 1201–1211

5.1. cAMP induced CCK transcription Many signals in the CNS are transduced via binding of ligands (hormones, neurotransmitters, neuropeptides) to their specific receptor, which activates receptor associated GTP-binding proteins (G-proteins). The Gs protein stimulates the activation of the enzyme adenylate cyclase, which converts ATP to cAMP. The major target of cAMP in most cells is the cAMP-dependent protein kinase A (PKA), which phosphorylates proteins that are involved in the control of a variety of biological function such as intermediary metabolism, cellular proliferation, and neuronal signaling [22,76]. The cAMP signaling pathway mainly stimulates gene transcription via activation of CREB associated with a CRE [45,77]. CREB is an ubiquitously expressed transcription factor involved in a variety of biological processes, including learning and memory [115] and neuronal cell survival [8,101]. CREB is phosphorylated on serine-133 in response to cAMP, and this phosphorylation is crucial for CREBmediated transcription [36]. Phosphorylated CREB subsequently recruits the transcriptional co-activator CREB-binding protein (CBP) [2,14,58], which serves as a transcriptional adaptor, linking phosphorylated CREB to the basal transcriptional machinery [52,58,81,121]. To study the role of the cAMP signaling pathway in CCK gene expression, forskolin, an activator of adenylate cyclase [113], was used. Forskolin was shown to be a potent activator of CCK transcription. Deletion or mutation of the CRE/TRE in the CCK promoter almost completely abolished activation, indicating that proteins binding the CRE/ TRE are mediating the effect by cAMP [41]. CREB, which binds to the CRE/TRE, was activated by cAMP via phosphorylation of serine-133, suggesting that transcriptional activation of CCK gene expression by cAMP involves phosphorylation of CREB serine-133. The significance of CREB in cAMP mediated CCK promoter activation was moreover examined by expression of a dominant negative CREB mutant, KCREB, which leads to the formation of inactive heterodimers with endogenous CREB [134]. KCREB almost completely inhibited forskolin induced CCK promoter activity, indicating that CREB is the main transcription factor involved in forskolin stimulated CCK transcription in SK-N-MC cells. These results are supported by examinations of the rat CCK promoter in STC-1 cells, which establishes a role for CREB in PACAP/cAMP mediated promoter activation [26]. As mentioned above PKA were originally suggested to be the main target of the cAMP pathway, leading to translocation of the catalytic domain of PKA into the nucleus, where it subsequently phosphorylates CREB [22]. However, recent results have shown that cAMP is able to activate the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathway [34,132,138] either via direct phosphorylation of the Ras family member Rap1 by PKA or via a family of cAMPbinding proteins that directly activates Rap1 [24,51,132].

1205

Indeed, cAMP activates the ERK MAPK signaling pathway in SK-N-MC [41]. However, also the p38 MAPK signaling pathway was activated in response to cAMP [39,41], suggesting that some of the cAMP effects on the CCK promoter are mediated via the ERK and p38 MAPK signaling pathways. 5.2. FGF-2 induced CCK transcription FGF-2 (also known as basic FGF) is produced in vast areas of the CNS [3], and is involved numerous effects in the nervous system, including cell migration, cell differentiation, neuronal survival and developmental processes [37]. In the rat, adult FGF-2 levels and patterns of distribution are reached at postnatal day 26 [57] and this coincides with the transmitter-active CCK peptides [74], suggesting that FGF-2 could play a role in CCK production in late development. FGF-2 stimulated CCK promoter activity, although not as potent as cAMP, and deletion and mutation of the CRE/ TRE abolished activation, suggesting that proteins binding the CRE/TRE also mediate the effect by FGF-2. Moreover, studies showed that CREB is activated by FGF-2 via phosphorylation of serine-133 [41]. The signaling pathways involved in this activation have moreover been examined. Receptor tyrosine kinases often transduce extracellular signals to the highly conserved MAPK signaling pathways. Mammalian cells contain at least three MAPK pathways, which regulate the activity of ERK MAPKs, the stress-activated protein kinase/c-Jun amino-terminal kinase (SAPK/JNK) MAPKs and the p38 MAPKs [102]. The proline directed MAPKs are structurally related and they are all activated by phosphorylation of a threonine- and tyrosine-rich motif in the so-called activation loop [29]. While the ERK MAPK cascade mainly is a target of receptor tyrosine kinases, the SAPK/JNK and p38 MAPKs are largely stimulated by cytokines and environmental stress. FGF-2 receptor binding is followed by receptor dimerization, autophosphorylation, and activation of the ERK MAPK signaling pathway in a Ras-dependent manner [55, 114,125]. In agreement with these results, FGF-2 mediated CCK promoter activation is inhibited by a dominant negative Ras mutant and by the MAP/ERK kinase 1 (MEK1) inhibitor PD98059, but also by the p38 MAPK inhibitor SB203580. These results indicates that FGF-2 activates both the ERK MAPK and the p38 MAPK signaling pathways via Ras and that the activation of these pathways are essential for FGF-2 mediated CCK promoter activation. Moreover, FGF-2 induced CREB phosphorylation and GAL4-CREB transcription were also reduced after treatment with PD98059 or SB203580. These results could indicate that the ERK and p38 MAPK pathways proceeds in parallel, which is in agreement with recent data showing that nerve growth factor (NGF) mediated phosphorylation of CREB also proceeds via the ERK and p38 MAPK path-

1206

T.v.O. Hansen / Peptides 22 (2001) 1201–1211

ways [137]. The signaling pathways that activates p38 is not completely understood, but since signaling can be inhibited by a dominant negative Ras mutant, it is possible that Ras controls p38 via activation of Rho [5]. The downstream activators of ERK and p38 MAPK includes pp90 ribosomal S6 kinase-2 (RSK2), the MAPK-activated protein kinase 2 (MAP-KAP kinase-2), and MSK1, respectively, which all have been demonstrated to phosphorylate CREB at serine133 [25,125,136,137]. Although the above study has focused on the effects by FGF-2, the mechanisms may be extended to NGF and brain-derived neurotrophic factor (BDNF), which have been demonstrated to activate the MAPK pathways in a similar way as FGF-2 [31,136,137]. 5.3. Synergistic activation of CCK transcription Previous results showed that cAMP and FGF-2 induced synergistic activation of CCK gene expression [41]. Synergy is generated by the convergens of forskolin, putative neurotransmitter substances or neuropeptides stimulating adenylate cyclase activity and cAMP production, which leads to the translocation of the catalytic subunit of PKA to the nucleus, and FGF-2 stimulating Ras, which activates the ERK MAPK and the p38 MAPK pathways. The cross-talk between PKA, ERK MAPK and p38 MAPK results in increased CREB activation via increased phosphorylation of serine-133, which ultimately leads to increased CCK transcription. The signaling pathways involved in CCK transcription in outlined in Fig. 3. Synergy between growth factors and neurotransmitters, coupling to the PKA signaling pathway, in control of neuropeptide expression may be of importance in several situations. Unlike most neurotransmitters, FGF-2 and other growth factors are not released from stored granules in short bursts, but are secreted in a constitutive manner over long time periods. During adult life it may be envisioned that the function of FGF-2 is mainly to upregulate the responses to the CCK promoter to neuropeptides and neurotransmitters that couple to the PKA signaling pathway. Moreover it is possible that cumulative actions may be relevant during regeneration in which FGF-2 and CCK have been demonstrated to be expressed in high levels [66,89].

6. Putative tissue-specific transcription factors involved in maturation of CCK-producing cells and in CCK gene expression As almost any other hormone from the enteroendocrine system CCK is expressed in both the gastrointestinal tissue and in the CNS. Cells from these two systems derive from the same endodermal stem cells [13,32,93], and the development of these cells are therefore thought to be partly dependent on the same transcription factors. Indeed, gene inactivation studies have shown that the transcription factors involved in maturation of cells and in regulation of

Fig. 3. Model of the signaling pathways leading to cumulative activation of the CCK gene promoter by FGF-2 and forskolin. Receptor binding of FGF-2 is followed by stimulation of Ras, which activates the ERK MAPK and the p38 MAPK pathways. The downstream activators of ERK and p38 includes pp90 ribosomal S6 kinase-2 (RSK-2), the MAPK-activated protein kinase-2 (MAPKAP kinase-2), and MSK1, respectively, which all have been demonstrated to phosphorylate CREB at serine-133 [25,125, 136,137]. Forskolin, putative neurotransmitter substances or neuropeptides stimulate adenylate cyclase activity and cAMP production, which leads to the translocation of the catalytic subunit of PKA to the nucleus, where it phosphorylates CREB on serine-133. Moreover, the PKA pathway activates ERK MAPK via Rap1, and p38 MAPK by a hereto unknown mechanism. Cross-talk between the PKA, ERK and p38 MAPK pathways results in increased CREB activation and ultimately to increased CCK transcription.

genes in the nervous system also are necessary for the normal differentiation of cells and for expression of hormones in the gut. Transgenic mice using 2.4 kb of CCK promoter sequence upstream of the transcription start site revealed that this promoter region is sufficient for correct CCK expression in CNS [47]. However, the regulatory elements and transcription factors involved in tissue-specific CCK gene expression and maturation of CCK-producing cells is currently unknown. Several transcription factors involved in differentiation of neurons and endocrine cells in the gut and in gene expression in these areas have been identified, and studies suggests that some of these transcription factors are involved in maturation of CCK-producing cells and in CCK gene expression as well, including NeuroD/BETA2 [64,84], Pax4 [133], and PDX-1 [65,72,87]. 6.1. NeuroD/BETA2 NeuroD/BETA2 is a cell-type specific bHLH transcription factor that is expressed in pancreatic endocrine cells, enteroendocrine cells in the intestine, including CCK-producing cells, and in the developing brain, where ectopic expression was shown to induce differentiation in the developing nervous system in frog embryos [64,84]. Mice carrying a targeted disruption of NeuroD/BETA2 gene developed severe diabetes and died perinatally, due to defects

T.v.O. Hansen / Peptides 22 (2001) 1201–1211

in insulin-producing aˆ-cell differentiation [83]. However, the development of CCK and secretin-producing endocrine cells throughout the intestine were also abolished in NeuroD/BETA2-null mice, whereas the expression of serotonin, glucagon, somatostatin and other neuroendocrine genes in enteroendocrine cells were unaffected [83]. Moreover, cells that normally express NeuroD/BETA2 is present in isolated mucosal intestinal epithelial cells, suggesting that NeuroD/ BETA2 may promote terminal differentiation of CCK-expressing enteroendocrine cells by activating CCK transcription. NeuroD/BETA2-null mice also display morphologic defects in the brain including the hippocampus and dentate gyrus, which leads to spontaneous limbic seizures [68,73, 111]. Since CCK is present in these areas, NeuroD/BETA2 could be involved in neuronal CCK gene expression as well. This is supported by preliminary results in neuroblastoma cells where NeuroD/BETA2 is able to activate CCK gene expression in co-transfection studies (T. v. O. Hansen, unpublished results). 6.2. Pax4 The Pax4 gene belong to a family of transcription factors that share a common conserved DNA-binding domain of 128 residues, called the paired box [133]. During mouse embryogenesis Pax4 expression is restricted to cells in the ventral spinal cord, endocrine pancreas, and intestine [62, 119]. Mice with a gene-inactivation of Pax4 died within 3 days of birth due to the absence of insulin and somatostatinproducing cells in the pancreas [119]. The targeted deletion of Pax4 moreover showed a dramatic decrease in gastrointestinal hormone expression in the duodenum, including CCK-producing cells [62], showing that Pax4 is essential for pancreatic and enteroendocrine cell differentiation.

1207

hormones. The core promoter contains a putative TATAbox and a juxtaposed GC-rich region, which probably is involved in the binding of the general transcription factor machinery. Currently, two regulatory elements involved in basal and regulated CCK transcription has been identified in the human CCK promoter region namely an E-box (-97 to -92) element and a combined CRE/TRE (-79 to -73) sequence. Transcription factors binding to these elements have been identified and include the bHLH-Zip protein USF1, which binds to the E-box element, and the bZip proteins CREB/ATF-1 that binds to the CRE/TRE sequence. Both USF1 and CREB increased CCK gene expression in co-transfection studies, suggesting that transcriptional regulation of the CCK gene is generated by the concerted action of factors binding to the E-box element and members of the CREB/ATF family of transcription factors binding to the CRE/TRE. The CCK promoter is also a target of extracellular signals, and growth factors and activators of the cAMP signaling pathway have been shown to synergistically stimulate CCK transcription via the p38 MAPK, the ERK MAPK, and PKA signaling pathways, respectively, resulting in enhanced phosphorylation and activation of CREB. These studies suggest that growth factors in combination with neurotransmitters/neuropeptides coupling to the PKA signaling pathway play an important role in the control of regulated endocrine and neuronal CCK gene expression. None of the so far identified transcription factors are likely to be involved in tissue-specific and developmental CCK gene expression. However, experiments suggest that NeuroD/BETA2 could be involved in these mechanisms and further studies should seek to unravel the role of this factor and others in spatial and temporal CCK expression.

6.3. PDX-1

Acknowledgments

PDX-1 (also known as IPF-1, STF-1 or IDX-1) is a homeodomain containing transcription factor expressed in developing pancreas, duodenum, stomach, and brain, while expression in the adult is restricted to the insulin-producing aˆ-cells, duodenal epithelium, and the antropyloric region of the stomach [60,65,72,87,112]. Mice carrying a targeted disruption of PDX-1 gene lack the pancreas and die within a few days after birth [49]. Moreover, malfunction of the upper duodenum occur in these mice, which often prevents gastric emptying, and analysis of the upper duodenum showed that the number of enteroendocrine cells, including CCK-producing cells, is reduced in this region [86]. These results show that PDX-1 is essential of pancreatic development, but also for the developmental program of the upper intestine.

I would like to thank Finn C. Nielsen, Jens F. Rehfeld and Lennart Friis-Hansen from the laboratory for their helpful comments, discussion, and critical reading of the manuscript.

7. Summary The CCK promoter regulates CCK gene expression during development, and in response to growth factors and

References [1] Angel P, Karin M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta 1991; 1072:129 –57. [2] Arias J, Alberts AS, Brindle P, Claret FX, Smeal T, Karin M, Feramisco J, Montminy M. Activation of cAMP and mitogen responsive genes relies on a common nuclear factor. Nature 1994;370: 226 –9. [3] Baird A. Fibroblast growth factors: activities and significance of non- neurotrophin neurotrophic growth factors. Curr Opin Neurobiol 1994;4:78 – 86. [4] Bardram L, Hilsted L, Rehfeld JF. Cholecystokinin, gastrin and their precursors in pheochromocytomas. Acta Endocrinol (Copenh) 1989; 120:479 – 84. [5] Bar-Sagi D, Hall A. Ras and Rho GTPases: a family reunion. Cell 2000;103:227–38.

1208

T.v.O. Hansen / Peptides 22 (2001) 1201–1211

[6] Beinfeld MC, Meyer DK, Brownstein MJ. Cholecystokinin in the central nervous system. Peptides 1981;2:77–9. [7] Blackwood EM, Kadonaga JT. Going the distance: a current view of enhancer action. Science 1998;281:61–3. [8] Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 1999; 286:1358 – 62. [9] Breathnach R, Chambon P. Organization and expression of eucaryotic split genes coding for proteins. Annu Rev Biochem 1981;50: 349 – 83. [10] Burazin TC, Gundlach AL. Rapid but transient increases in cholecystokinin mRNA levels in cerebral cortex following amygdaloidkindled seizures in the rat. Neurosci Lett 1996;209:65– 8. [11] Burke TW, Kadonaga JT. Drosophila TFIID binds to a conserved downstream basal promoter element that is present in many TATAbox-deficient promoters. Genes Dev 1996;10:711–24. [12] Burley SK, Roeder RG. Biochemistry and structural biology of transcription factor IID (TFIID). Annu Rev Biochem 1996; 65:769 – 99. [13] Cheng H, Leblond CP. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian Theory of the origin of the four epithelial cell types. Am J Anat 1974;141:537– 61. [14] Chrivia JC, Kwok RP, Lamb N, Hagiwara M, Montminy MR, Goodman RH. Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 1993;365:855–9. [15] Comb M., Birnberg NC, Seasholtz A, Herbert E, Goodman HM. A cyclic AMP- and phorbol ester-inducible DNA element. Nature 1986;323:353– 6. [16] Comb M, Mermod N, Hyman SE, Pearlberg J, Ross ME, Goodman HM. Proteins bound at adjacent DNA elements act synergistically to regulate human proenkephalin cAMP inducible transcription. EMBO J 1988; 7:3793– 805. [17] Cordier-Bussat M, Bernard C, Haouche S, Roche C, Abello J, Chayvialle JA, Cuber JC. Peptones stimulate cholecystokinin secretion and gene transcription in the intestinal cell line STC-1. Endocrinology 1997;138:1137– 44. [18] Courey, A. J., Tjian, R. Mechanisms of transcriptional control as revealed by studies of human transcription factor Sp1. In: McKnight SL, Yamamoto KR, editors. Transcriptional regulation. New York: Cold Spring Habor University Press, 1992. p. 743– 69. [19] Crawley JN. Comparative distribution of cholecystokinin and other neuropeptides. Why is this peptide different from all other peptides? Ann N Y Acad Sci 1985;448:1– 8. [20] Crawley JN, Corwin RL. Biological actions of cholecystokinin. Peptides 1994;15:731–55. [21] Croll SD, Wiegand SJ, Anderson KD, Lindsay RM, Nawa H. Regulation of neuropeptides in adult rat forebrain by the neurotrophins BDNF and NGF. Eur J Neurosci 1994; 6:1343–53. [22] Daniel PB, Walker WH, Habener JF. Cyclic AMP signaling and gene regulation. Annu Rev Nutr 1998;18:353– 83. [23] De Belleroche J, Bandopadhyay R, King A, Malcolm AD, O’Brien K, Premi BP, Rashid A. Regional distribution of cholecystokinin messenger RNA in rat brain during development: quantitation and correlation with cholecystokinin immunoreactivity. Neuropeptides 1990;15:201–12. [24] de Rooij J, Zwartkruis FJ, Verheijen MH, Cool RH, Nijman SM, Wittinghofer A, Bos JL. Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature 1998; 396: 474 –7. [25] Deak M, Clifton AD, Lucocq LM, Alessi DR. Mitogen- and stressactivated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J 1998; 17:4426 – 41.

[26] Deavall DG, Raychowdhury R, Dockray GJ, Dimaline R. Control of CCK gene transcription by PACAP in STC-1 cells. Am J Physiol Gastrointest Liver Physiol 2000;279:G605–12. [27] Deschenes RJ, Haun RS, Funckes CL, Dixon JE. A gene encoding rat cholecystokinin. Isolation, nucleotide sequence, and promoter activity. J Biol Chem 1985;260:1280 – 6. [28] Deschenes RJ, Lorenz LJ, Haun RS, Roos BA, Collier KJ, Dixon JE. Cloning and sequence analysis of a cDNA encoding rat preprocholecystokinin. Proc Natl Acad Sci U S A 1984;81:726 –30. [29] Dhanasekaran N, Premkumar Reddy E. Signaling by dual specificity kinases. Oncogene 1998;17:1447–55. [30] Ding XZ, Mocchetti I. Dopaminergic regulation of cholecystokinin mRNA content in rat striatum. Brain Res Mol Brain Res 1992;12: 77– 83. [31] Finkbeiner S, Tavazoie SF, Maloratsky A, Jacobs KM, Harris KM, Greenberg ME. CREB: a major mediator of neuronal neurotrophin responses. Neuron 1997;19:1031– 47. [32] Fontaine J, Le Douarin NM. Analysis of endoderm formation in the avian blastoderm by the use of quail-chick chimaeras. The problem of the neurectodermal origin of the cells of the APUD series. J Embryol Exp Morphol 1977;41:209 –22. [33] Friedman J, Schneider BS, Powell D. Differential expression of the mouse cholecystokinin gene during brain and gut development. Proc Natl Acad Sci U S A 1985;82:5593–7. [34] Frodin M, Peraldi P, Van Obberghen E. Cyclic AMP activates the mitogen-activated protein kinase cascade in PC12 cells. J Biol Chem 1994;269:6207–14. [35] Ghatei MA, Sheppard MN, O’Shaughnessy DJ, Adrian TE, McGregor GP, Polak JM, Bloom SR. Regulatory peptides in the mammalian respiratory tract. Endocrinology 1982;111:1248 –54. [36] Gonzalez GA, Montminy MR. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 1989;59:675– 80. [37] Gremo F, Presta M. Role of fibroblast growth factor-2 in human brain: a focus on development. Int J Dev Neurosci 2000; 18:271–9. [38] Gruber B, Greber S, Sperk G. Kainic acid seizures cause enhanced expression of cholecystokinin- octapeptide in the cortex and hippocampus of the rat. Synapse 1993; 15:221– 8. [39] Hansen TVO, Rehfeld JF, Nielsen FC. Cyclic AMP-induced neuronal differentiation via activation of p38 mitogen-activated protein kinase. J Neurochem 2000;75:1870 –7. [40] Hansen TVO, Rehfeld JF, Nielsen FC. Function of the C-36 to T polymorphism in the human cholecystokinin gene promoter. Mol Psychiatry 2000;5:443–7. [41] Hansen TVO, Rehfeld JF, Nielsen FC. Mitogen-activated protein kinase and protein kinase A signaling pathways stimulate cholecystokinin transcription via activation of cyclic adenosine 3⬘,5⬘-monophosphate response element-binding protein. Mol Endocrinol 1999; 13:466 –75. [42] Harada S, Okubo T, Tsutsumi M, Takase S, Muramatsu T. A new genetic variant in the Sp1 binding cis-element of cholecystokinin gene promoter region and relationship to alcoholism. Alcohol Clin Exp Res 1998;22:93S–96S. [43] Hasegawa M, Usui H, Araki K, Kuwano R, Takahashi Y. Developmental and regional changes of cholecystokinin mRNA in rat brains. FEBS Lett 1986;194:224 – 6. [44] Haun RS, Dixon JE. A transcriptional enhancer essential for the expression of the rat cholecystokinin gene contains a sequence identical to the -296 element of the human c-fos gene. J Biol Chem 1990;265:15455– 63. [45] Hoeffler JP, Meyer TE, Yun Y, Jameson JL, Habener JF. Cyclic AMP-responsive DNA-binding protein: structure based on a cloned placental cDNA. Science 1988;242:1430 –3. [46] Holland K, Norell A, Micevych P. Interaction of thyroxine and estrogen on the expression of estrogen receptor alpha, cholecystokinin, and preproenkephalin messenger ribonucleic acid in the limbic-hypothalamic circuit. Endocrinology 1998;139:1221– 8.

T.v.O. Hansen / Peptides 22 (2001) 1201–1211 [47] Itoh Y, Kozakai I, Toyomizu M, Ishibashi T, Kuwano R. Mapping of cholecystokinin transcription in transgenic mouse brain using Escherichia coli ␤-galactosidase reporter gene. Dev Growth Differ 1998;40:395– 402. [48] Johnsen AH, Jonson L, Rourke IJ, Rehfeld JF. Elasmobranchs express separate cholecystokinin and gastrin genes. Proc Natl Acad Sci U S A 1997;94:10221– 6. [49] Jonsson J, Carlsson L, Edlund T, Edlund H. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 1994;371: 606 –9. [50] Katsel PL, Greenstein RJ. Identification of overlapping AP-2/NFkappaB responsive elements on the rat cholecystokinin gene promoter. J Biol Chem; In press [51] Kawasaki H, Springett GM, Mochizuki N, Toki S, Nakaya M, Matsuda M, Housman DE, Graybiel AM. A family of cAMPbinding proteins that directly activate Rap1. Science 1998;282: 2275–9. [52] Kee BL, Arias J, Montminy MR. Adaptor-mediated recruitment of RNA polymerase II to a signal-dependent activator. J Biol Chem 1996;271:2373–5. [53] Kim J, Struhl K. Determinants of half-site spacing preferences that distinguish AP-1 and ATF/CREB bZIP domains. Nucleic Acids Res 1995;23:2531–7. [54] Konradi C, Kobierski LA, Nguyen TV, Heckers S, Hyman SE. The cAMP-response-element-binding protein interacts, but Fos protein does not interact, with the proenkephalin enhancer in rat striatum. Proc Natl Acad Sci U S A 1993;90:7005–9. [55] Kouhara H, Hadari YR, Spivak-Kroizman T, Schilling J, Bar-Sagi D, Lax I, Schlessinger J. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell 1997;89:693–702. [56] Kretzner L, Blackwood EM, Eisenman RN. Myc and Max proteins possess distinct transcriptional activities. Nature 1992;359:426 –9. [57] Kuzis K, Reed S, Cherry NJ, Woodward WR, Eckenstein FP. Developmental time course of acidic and basic fibroblast growth factors’ expression in distinct cellular populations of the rat central nervous system. J Comp Neurol 1995;358:142–53. [58] Kwok RP, Lundblad JR, Chrivia JC, Richards JP, Bachinger HP, Brennan RG, Roberts SG, Green MR, Goodman RH. Nuclear protein CBP is a coactivator for the transcription factor CREB. Nature 1994;370:223– 6. [59] Lagrange T, Kapanidis AN, Tang H, Reinberg D, Ebright RH. New core promoter element in RNA polymerase II-dependent transcription: sequence-specific DNA binding by transcription factor IIB. Genes Dev 1998;12:34 – 44. [60] Larsson LI, Madsen OD, Serup P, Jonsson J, Edlund H. Pancreaticduodenal homeobox 1 -role in gastric endocrine patterning. Mech Dev 1996;60:175– 84. [61] Larsson LI, Rehfeld JF. Localization and molecular heterogeneity of cholecystokinin in the central and peripheral nervous system. Brain Res 1979;165:201–18. [62] Larsson LI, St-Onge L, Hougaard DM, Sosa-Pineda B, Gruss P. Pax 4 and 6 regulate gastrointestinal endocrine cell development. Mech Dev 1998;79:153–9. [63] Lay JM, Gillespie PJ, Samuelson LC. Murine prenatal expression of cholecystokinin in neural crest, enteric neurons, and enteroendocrine cells. Dev Dyn 1999;216:190 –200. [64] Lee JE, Hollenberg SM, Snider L, Turner DL, Lipnick N, Weintraub H. Conversion of Xenopus ectoderm into neurons by NeuroD, a basic helix-loop-helix protein. Science 1995;268:836 – 44. [65] Leonard J, Peers B, Johnson T, Ferreri K, Lee S, Montminy MR. Characterization of somatostatin transactivating factor-1, a novel homeobox factor that stimulates somatostatin expression in pancreatic islet cells. Mol Endocrinol 1993;7:1275– 83. [66] Leonard S, Luthman D, Logel J, Luthman J, Antle C, Freedman R, Hoffer B. Acidic and basic fibroblast growth factor mRNAs are increased in striatum following MPTP-induced dopamine neurofiber

[67]

[68]

[69]

[70]

[71] [72]

[73]

[74]

[75]

[76] [77]

[78]

[79] [80]

[81]

[82]

[83]

[84]

[85]

[86]

1209

lesion: assay by quantitative PCR. Brain Res Mol Brain Res 1993; 18:275– 84. Liddle RA, Carter JD, McDonald AR. Dietary regulation of rat intestinal cholecystokinin gene expression. J Clin Invest 1988;81: 2015–9. Liu M, Pleasure SJ, Collins AE, Noebels JL, Naya FJ, Tsai MJ, Lowenstein DH. Loss of BETA2/NeuroD leads to malformation of the dentate gyrus and epilepsy. Proc Natl Acad Sci U S A 2000;97: 865–70. Luscher B, Larsson LG. The basic region/helix-loop-helix/leucine zipper domain of Myc proto- oncoproteins: function and regulation. Oncogene 1999;18:2955– 66. Luttichau HR, Van Solinge WW, Nielsen FC, Rehfeld JF. Developmental expression of the gastrin and cholecystokinin genes in rat colon. Gastroenterology 1993;104:1092– 8. Massari ME, Murre C. Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms. Mol Cell Biol 2000;20:429 – 40. Miller CP, McGehee RE, Jr, Habener JF. IDX-1: a new homeodomain transcription factor expressed in rat pancreatic islets and duodenum that transactivates the somatostatin gene. EMBO J 1994; 13:1145–56. Miyata T, Maeda T, Lee JE. NeuroD is required for differentiation of the granule cells in the cerebellum and hippocampus. Genes Dev 1999;13:1647–52. Mogensen NW, Hilsted L, Bardram L, Rehfeld JF. Procholecystokinin processing in rat cerebral cortex during development. Brain Res Dev Brain Res 1990;54:81– 6. Monstein HJ, Folkesson R, Geijer T. Procholecystokinin and proenkephalin A mRNA expression is modulated by cyclic AMP and noradrenaline. J Mol Endocrinol 1990;4:37– 41. Montminy M. Transcriptional regulation by cyclic AMP. Annu Rev Biochem 1997;66:807–22. Montminy MR, Bilezikjian LM. Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene. Nature 1987;328:175– 8. Mutoh H, Ratineau C, Ray S, Leiter AB. Transcriptional events controlling the terminal differentiation of intestinal endocrine cells. Aliment Pharmacol Ther 2000;14(Suppl 1):170 –5. Myer VE, Young RA. RNA polymerase II holoenzymes and subcomplexes. J Biol Chem 1998;273:27757– 60. Nakajima N, Horikoshi M, Roeder RG. Factors involved in specific transcription by mammalian RNA polymerase II: purification, genetic specificity, and TATA box-promoter interactions of TFIID. Mol Cell Biol 1988;8:4028 – 40. Nakajima T, Uchida C, Anderson SF, Lee CG, Hurwitz J, Parvin JD, Montminy M. RNA helicase A mediates association of CBP with RNA polymerase II. Cell 1997;90:1107–12. Nawa H, Pelleymounter MA, Carnahan J. Intraventricular administration of BDNF increases neuropeptide expression in newborn rat brain. J Neurosci 1994;14:3751– 65. Naya FJ, Huang HP, Qiu Y, Mutoh H, DeMayo FJ, Leiter AB, Tsai MJ. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev 1997;11:2323–34. Naya FJ, Stellrecht CM, Tsai MJ. Tissue-specific regulation of the insulin gene by a novel basic helix-loop-helix transcription factor. Genes Dev 1995;9:1009 –19. Nielsen FC, Pedersen K, Hansen TVO, Rourke IJ, Rehfeld JF. Transcriptional regulation of the human cholecystokinin gene: composite action of upstream stimulatory factor, Sp1, and members of the CREB/ATF-AP-1 family of transcription factors. DNA Cell Biol 1996;15:53– 63. Offield MF, Jetton TL, Labosky PA, Ray M, Stein RW, Magnuson MA, Hogan BL, Wright C. V. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 1996;122:983–95.

1210

T.v.O. Hansen / Peptides 22 (2001) 1201–1211

[87] Ohlsson H, Karlsson K, Edlund T. IPF1, a homeodomain-containing transactivator of the insulin gene. EMBO J 1993;12:4251–9. [88] Okubo T, Harada S, Higuchi S, Matsushita S. Genetic association between alcohol withdrawal symptoms and polymorphism of CCK gene promoter. Alcohol Clin Exp Res 1999;23:11S–12S. [89] Palkovits M. Neuropeptide messenger plasticity in the CNS neurons following axotomy. Mol Neurobiol 1995;10:91–103. [90] Pelto-Huikko M, Persson H, Schalling M, Rehfeld JF, Hokfelt T. Immunocytochemical demonstration of cholecystokinin-like immunoreactivity in spermatozoa in monkey testis and epididymis. Acta Physiol Scand 1989;137:465– 6. [91] Persson H, Rehfeld JF, Ericsson A, Schalling M, Pelto-Huikko M, Hokfelt T. Transient expression of the cholecystokinin gene in male germ cells and accumulation of the peptide in the acrosomal granule: possible role of cholecystokinin in fertilization. Proc Natl Acad Sci U S A 1989;86:6166 –70. [92] Ratineau C, Roche C, Chuzel F, Cordier-Bussai M, Blanc M, Bernard C, Cuber JC, Chayvialle JA. Regulation of intestinal cholecystokinin gene expression by glucocorticoids. J Endocrinol 1996;151: 137– 45. [93] Rawdon BB, Andrew A. Origin and differentiation of gut endocrine cells. Histol Histopathol 1993;8:567– 80. [94] Rehfeld JF. Accumulation of nonamidated preprogastrin and preprocholecystokinin products in porcine pituitary corticotrophs. Evidence of post-translational control of cell differentiation. J Biol Chem 1986;261:5841–7. [95] Rehfeld JF. Cholecystokinin. In: Schultz SG, Makhlouf GM, Rauner D, editors. Handbook of Physiology: The Gastrointestinal System. Bethesda: American Physiological Society, 1989. p. 337–358. [96] Rehfeld JF. Immunochemical studies on cholecystokinin. II. Distribution and molecular heterogeneity in the central nervous system and small intestine of man and hog. J Biol Chem 1978;253:4022–30. [97] Rehfeld JF, Bardram L, Hilsted L. Ontogeny of procholecystokinin maturation in rat duodenum, jejunum, and ileum. Gastroenterology 1992;103:424 –30. [98] Rehfeld JF, Johnsen AH, Odum L, Bardram L, Schifter S, Scopsi L. Non-sulphated cholecystokinin in human medullary thyroid carcinomas. J Endocrinol 1990;124:501– 6. [99] Rehfeld JF, Lindholm J, Andersen BN, Bardram L, Cantor P, Fenger M, Ludecke DK. Pituitary tumors containing cholecystokinin. N Engl J Med 1987;316:1244 –7. [100] Rehfeld JF, Nielsen FC. Molecular forms and regional distribution of cholecystokinin in the central nervous system. In: Bradwejn J, Vasar E, editors. Cholecystokinin and anxiety: From neuron to behaviour. Heidelberg: Springer-Verlag, 1995. p. 33–56. [101] Riccio A, Ahn S, Davenport CM, Blendy JA, Ginty DD. Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. Science 1999;286:2358 – 61. [102] Robinson MJ, Cobb MH. Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 1997;9:180 – 6. [103] Roeder RG. Role of general and gene-specific cofactors in the regulation of eukaryotic transcription. Cold Spring Harb Symp Quant Biol 1998;63:201–18. [104] Roeder RG. The role of general initiation factors in transcription by RNA polymerase II. Trends Biochem Sci 1996;21:327–35. [105] Rourke IJ, Hansen TVO, Nerlov C, Rehfeld JF, Nielsen FC. Negative cooperativity between juxtaposed E-box and cAMP/TPA responsive elements in the cholecystokinin gene promoter. FEBS Lett 1999;448:15– 8. [106] Rourke IJ, Rehfeld JF, Moller M, Johnsen AH. Characterization of the cholecystokinin and gastrin genes from the bullfrog, Rana catesbeiana: evolutionary conservation of primary and secondary sites of gene expression. Endocrinology 1997;138:1719 –27. [107] Sassone-Corsi P, Ransone LJ, Verma IM. Cross-talk in signal transduction: TPA-inducible factor jun/AP-1 activates cAMP-responsive enhancer elements. Oncogene 1990; 5:427–31.

[108] Sawadogo M, Roeder RG. Interaction of a gene-specific transcription factor with the adenovirus major late promoter upstream of the TATA box region. Cell 1985;43:165–75. [109] Schiffmann SN, Vanderhaeghen JJ. Distribution of cells containing mRNA encoding cholecystokinin in the rat central nervous system. J Comp Neurol 1991;304:219 –33. [110] Schonthal A, Buscher M, Angel P, Rahmsdorf HJ, Ponta H, Hattori K, Chiu R, Karin M, Herrlich P. The Fos and Jun/AP-1 proteins are involved in the downregulation of Fos transcription. Oncogene 1989;4:629 –36. [111] Schwab MH, Bartholomae A, Heimrich B, Feldmeyer D, DruffelAugustin S, Goebbels S, Naya FJ, Zhao S, Frotscher M, Tsai MJ, Nave KA. Neuronal basic helix-loop-helix proteins (NEX and BETA2/Neuro D) regulate terminal granule cell differentiation in the hippocampus. J Neurosci 2000;20:3714 –24. [112] Schwartz PT, Perez-Villamil B, Rivera A, Moratalla R, Vallejo M. Pancreatic homeodomain transcription factor IDX1/IPF1 expressed in developing brain regulates somatostatin gene transcription in embryonic neural cells. J Biol Chem 2000;275:19106 –14. [113] Seamon KB, Padgett W, Daly JW. Forskolin: unique diterpene activator of adenylate cyclase in membranes and in intact cells. Proc Natl Acad Sci U S A 1981;78:3363–7. [114] Shaoul E, Reich-Slotky R, Berman B, Ron D. Fibroblast growth factor receptors display both common and distinct signaling pathways. Oncogene 1995;10:1553– 61. [115] Silva AJ, Kogan JH, Frankland PW, Kida S. CREB and memory. Annu Rev Neurosci 1998;21:127– 48. [116] Simerly RB, Young BJ, Capozza MA, Swanson LW. Estrogen differentially regulates neuropeptide gene expression in a sexually dimorphic olfactory pathway. Proc Natl Acad Sci U S A 1989;86: 4766 –70. [117] Sirito M, Lin Q, Maity T, Sawadogo M. Ubiquitous expression of the 43- and 44-kDa forms of transcription factor USF in mammalian cells. Nucleic Acids Res 1994;22:427–33. [118] Smale ST, Baltimore D. The “initiator” as a transcription control element. Cell 1989;57:103–13. [119] Sosa-Pineda B, Chowdhury K, Torres M, Oliver G, Gruss P. The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature 1997;386:399 – 402. [120] Suske G. The Sp-family of transcription factors. Gene 1999;238: 291–300. [121] Swope DL, Mueller CL, Chrivia JC. CREB-binding protein activates transcription through multiple domains. J Biol Chem 1996; 271:28138 – 45. [122] Takahashi Y, Fukushige S, Murotsu T, Matsubara K. Structure of human cholecystokinin gene and its chromosomal location. Gene 1986;50:353– 60. [123] Takahashi Y, Kato K, Hayashizaki Y, Wakabayashi T, Ohtsuka E, Matsuki S, Ikehara M, Matsubara K. Molecular cloning of the human cholecystokinin gene by use of a synthetic probe containing deoxyinosine. Proc Natl Acad Sci U S A 1985;82:1931–5. [124] Takeda K, Koshimoto H, Uchiumi F, Haun RS, Dixon JE, Kato T. Postnatal development of cholecystokinin-like immunoreactivity and its mRNA level in rat brain regions. J Neurochem 1989;53: 772– 8. [125] Tan Y, Rouse J, Zhang A, Cariati S, Cohen P, Comb MJ. FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. EMBO J 1996;15:4629 – 42. [126] Triezenberg SJ. Structure and function of transcriptional activation domains. Curr Opin Genet Dev 1995;5:190 – 6. [127] Van Dyke MW, Roeder RG, Sawadogo M. Physical analysis of transcription preinitiation complex assembly on a class II gene promoter. Science 1988;241:1335– 8. [128] van Solinge WW, Rehfeld JF. Co-transcription of the gastrin and cholecystokinin genes with selective translation of gastrin mRNA in a human gastric carcinoma cell line. FEBS Lett 1992;309:47–50. [129] Vinson CR, Sigler PB, McKnight SL. Scissors-grip model for DNA

T.v.O. Hansen / Peptides 22 (2001) 1201–1211

[130]

[131]

[132]

[133]

[134]

recognition by a family of leucine zipper proteins. Science 1989; 246:911– 6. Viollet B, Lefrancois-Martinez AM, Henrion A, Kahn A, Raymondjean M, Martinez A. Immunochemical characterization and transacting properties of upstream stimulatory factor isoforms. J Biol Chem 1996;71:1405–15. Vitale M, Vashishtha A, Linzer E, Powell DJ, Friedman JM. Molecular cloning of the mouse CCK gene: expression in different brain regions and during cortical development. Nucleic Acids Res 1991;19:169 –77. Vossler MR, Yao H, York RD, Pan MG, Rim CS, Stork PJ. cAMP activates MAP kinase and Elk-1 through a B-Raf- and Rap1-dependent pathway. Cell 1997;89:73– 82. Walther C, Guenet JL, Simon D, Deutsch U, Jostes B, Goulding MD, Plachov D, Balling R, Gruss P. Pax: a murine multigene family of paired box-containing genes. Genomics 1991;11:424 –34. Walton KM, Rehfuss RP, Chrivia JC, Lochner JE, Goodman RH. A dominant repressor of cyclic adenosine 3⬘,5⬘-monophosphate (cAMP)-regulated enhancer-binding protein activity inhibits the cAMP-mediated induction of the somatostatin promoter in vivo. Mol Endocrinol 1992;6:647–55.

1211

[135] Wang Z, Valdes J, Noyes R, Zoega T, Crowe RR. Possible association of a cholecystokinin promotor polymorphism (CCK- 36CT) with panic disorder. Am J Med Genet 1998;81:228 –34. [136] Xing J, Ginty DD, Greenberg ME. Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science 1996;273:959 – 63. [137] Xing J, Kornhauser JM, Xia Z, Thiele EA, Greenberg ME. Nerve growth factor activates extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways to stimulate CREB serine 133 phosphorylation. Mol Cell Biol 1998;18:1946 – 55. [138] Yao H, York RD, Misra-Press A, Carr DW, Stork PJ. The cyclic adenosine monophosphate-dependent protein kinase (PKA) is required for the sustained activation of mitogen-activated kinases and gene expression by nerve growth factor. J Biol Chem 1998;273: 8240 –7. [139] Zhang LX, Smith MA, Kim SY, Rosen JB, Weiss SR, Post RM. Changes in cholecystokinin mRNA expression after amygdala kindled seizures: an in situ hybridization study. Brain Res Mol Brain Res 1996;35:278 – 84.