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a Fondation pour Recherches Médicales, University of Geneva, 1211 Geneva, Switzerland
b Department of Nutrition, University of Montreal and the CHUM, Centre de Recherche L. C. Simard and Institut du Cancer, Montreal, QC H2L 4M1, Canada
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: glucagon-like peptide-1 • pituitary adenylate cyclase-activating polypeptide • immediate-early response genes • proto-oncogenes • intracellular Ca2+
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Neurohormonal agonists also modulate insulin secretion and ß-cell growth. Among the hormones and neurotransmitters influencing ß-cell intracellular signaling, activators of adenylyl cyclase such as glucagon-like peptide 1 (GLP-1) and pituitary adenylate cyclase-activating polypeptide (PACAP-38) are potent glucoincretins amplifying the insulin secretory effect of glucose at physiological concentrations of the sugar. GLP-1 acts as a competence factor in determining the ability of the ß-cell to respond to glucose both in terms of ATP-dependent potassium channel closure and insulin release, since cAMP allows a secretory response to the sugar in glucose-unresponsive ß-cells (6, 7). GLP-1 is considered as a potentially important hormone in the treatment of type II diabetes (8). This peptide is also an insulinotropic factor by virtue of its action on insulin gene transcription and biosynthesis (9), but whether it also influences ß-cell growth, as do other cAMP agonists (10), is not known at this time.
If much knowledge has accumulated recently on the short-term action of glucose on ß-cell signaling (11), the mechanisms implicated in the adaptive responses to the sugar remain largely unknown. Since these responses are long-term processes, they are likely to involve changes in the expression of transcription factors, which, in turn, might regulate many secondary genes such as metabolic and cell-cycle genes. Glucose activates the mitogen-activated protein (MAP) -kinase pathway in INS-1 cells in a cAMP-dependent manner (12).
To link glucose signaling to the late phenotypic actions of the sugar, we have investigated whether glucose causes a rapid induction of immediate early-response genes (IEGs) coding for known transcription factors implicated in the regulation of cell growth and differentiation. Since Ca2+ plays a central role in ß-cell activation (13) we chose, as a paradigm of IEG activation by glucose, to study five candidate genes (c-fos, c-jun, junB, zif-268, and nur-77) that in other cell systems have been documented to be particularly induced by Ca2+ agonists (14). Members of the Fos and Jun family of proteins dimerize to form the AP-1 transcription factor, which regulates many secondary genes, including metabolic genes (15). Nur-77 is an orphan nuclear receptor encoding a member of the steroid hormone superfamily. It shows a pronounced induction by Ca2+ in PC12 cells (16) and appears to play a role in T lymphocyte apoptosis (17). Zif-268 is a 3 zinc finger protein encoding a member of the GSG family of transcription factors (18).
In this study we show that glucose, at physiological concentrations, causes a Ca2+-dependent transcriptional activation of the c-fos, c-jun, JunB, zif-268, and nur-77 genes. Furthermore, the incretins GLP-1 and PACAP-38 synergize with glucose in this inductive process and act as competence factors.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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[32P]dCTP (3000 Ci/mmol) and nylon hybridization membranes were obtained from Amersham (Arlington Heights, Ill.). Random priming kits were from Qiagen (Chatsworth, Calif.).
Cell culture and incubation
INS-1 cells were grown in monolayer cultures with regular RPMI medium supplemented with 10 mM HEPES, 10% heat-inactivated fetal calf serum, 2 mM L-glutamine, 100 IU/ml penicillin, 100 µg/ml streptomycin, 1 mM sodium pyruvate, and 50 µM ß-mercaptoethanol at 37°C in a humidified (5% CO2, 95% air) atmosphere (19). Cells (1.4 x 106) were seeded 7 days before use in 15 x 60 mm petri dishes. When INS-1 cells reached approximately 80% confluence, they were washed twice with 11 mM phosphate-buffered saline (pH 7.0, 37°C) and preincubated at 37°C for 90 min in a Krebs-Ringer medium (KRB) at low (3 mM) glucose. Cells were incubated in the same KRB medium containing various test substances. ßHC9 cells were obtained from Dr. D. Hanahan (UCSF) and cultured in Dulbecco's modified Eagle's medium with 25 mM glucose (20). Twenty-four hours before stimulation, cells were cultured at 5 mM glucose. All other culture specifications were identical to those described above for INS-1.
mRNA measurements and in vitro transcription assays
Total RNA was extracted from cells by the guanidium isothiocyanate method. RNA samples (12 µg) were denatured by incubation in glyoxal, subjected to electrophoresis in 1.2% agarose gels, and transferred to a nylon membrane by capillarity. mRNAs were detected by Northern blot hybridization with 32P-labeled cDNA probes obtained by random priming. The inserts used were: a nur-77 EcoRI 1056–2456 EcoRI fragment from mouse subcloned in plasmid pBSKS; a c-fos EcoRI 1–2116 EcoRI fragment from rat subcloned in plasmid pSP65; a JunB BamHI 423–1576 EcoRI fragment from mouse subcloned in plasmid pGEM-2; a zif-268 EcoRI 1–3200 EcoRI fragment from mouse subcloned in plasmid pBSKS+; a c-jun EcoRI 1–2600 EcoRI fragment from mouse subcloned in plasmid pGEM-2. Human alpha-actin PstI 1–720 PvuII was used to normalize early gene mRNA levels. All membranes were Coomassie blue stained as another means to normalize mRNA levels and analyzed with a Molecular Dynamics PhosphorImager to quantify mRNA accumulation.
Run-on transcription assays using INS-1 cells nuclei were performed as described in ref 3. Nascent transcripts were elongated in the presence of [32P]UTP and 2.1 mg/ml heparin. The resulting [32P]-labeled RNAs were subjected to mild alkaline hydrolysis (30 min at 50°C in the presence of 50 mM Na2CO3) and subsequently hybridized to 2 µg/dot of the following DNA construction immobilized on nitrocellulose membrane: a 0.74 kb EcoR1-BamH1 fragment (position 1040–1780) of mouse 18S rRNA cDNA subcloned in pUC830, a 0.5 kb EcoR1-EcoR1 fragment of mouse nur-77 cDNA subcloned in pGEM-2 (kindly provided by Dr L. Lau, University of Illinois), and a 0.438 kb EcoR1-Sal1 fragment (position 1–438) of rat c-fos c-DNA subcloned in pBSKS, a 1576 kb EcoR1-EcoR1 fragment (position 1–1576) of mouse JunB c-DNA subcloned in pGEM-2.
Measurement of cAMP production
After cell washing, cellular adenine nucleotides were radiolabeled by preincubating INS-1 cells for 2 h in KRB medium containing 1.5 µCi/ml [3H]adenine (10–20 Ci/mmol). Cells were subsequently washed and preincubated for 15 min at 37°C in 3 ml of KRB containing the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (1 mM). Test substances were then added and cells were further incubated for the indicated times. The reaction was stopped by replacing the medium with 300 µl 30% trichloroacetic acid and then adding 800 µl of a solution containing 0.1 mM cAMP (as a carrier) and 3000 cpm [14C]cAMP (50 mCi/mmol) to monitor cAMP recovery. cAMP was separated from other adenine derivatives by running the reaction mixture sequentially through Dowex and alumina columns (21). All conditions were performed in triplicate, and the results were calculated as percent ([3H]cAMP)/(total [3H]adenine derivatives).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Fig. 1
indicate that 0.5 mM of the membrane-permeant cAMP analog cpt-cAMP, which activates cAMP-dependent protein kinase, caused an accumulation of the c-jun, nur-77, zif-268, JunB, and c-fos transcripts. Although glucose alone had no effect, high glucose (15 mM) amplified the cAMP inductive process by 100%. A typical actin blot is shown as a control of the amount of RNA present in each lane (10 µg of RNA).
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The concentration dependence of glucose, in the presence of cpt-cAMP (0.5 mM), on the accumulation of the nur-77, JunB, and c-fos transcripts is shown in Fig. 2A.
A rise of glucose from 3 to only 6 mM induced a marked increase in the expression level of the nur-77, JunB, and c-fos mRNAs. The most effective concentration of the sugar was 11 mM; higher concentrations caused somewhat less effect. Provided coincident stimulation of the cAMP signaling pathway, INS-1 cells respond in terms of IEG induction in a manner very sensitive to glucose. In the presence of 11 mM of glucose, the effect of cpt-cAMP on IEG induction was dose dependent ( Fig. 2B). A rise in the levels of these three mRNA species occurred at 0.1 mM cpt-cAMP. Half-maximal and maximal inductions were observed at 0.3 and 0.5 mM cpt-cAMP, respectively.
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Kinetics of IEG induction by glucose and cpt-cAMP
The time dependence of the accumulation of the nur-77, JunB, and c-fos transcripts in the presence of cpt-cAMP at low and high glucose are shown in Fig. 3
A, B. The transcripts of all three IEGs are induced after a lag time of about 30 min, show significantly elevated levels after 60 min, and continue to accumulate in the second hour after stimulation. The kinetics of mRNA accumulation of the three IEGs are similar at low ( Fig. 3A) and high glucose ( Fig. 3B); glucose potentiates the effects of cAMP at 60 and 120 min. Thus, IEG induction by cAMP and elevated glucose occurs in a concerted manner; it was slow in onset and sustained over 2 h. In contrast, when pharmacological stimulants that act on the PKA (forskolin), the PKC (PMA), and the intracellular Ca2+ (ionomycin) signaling systems were used to maximally activate INS-1 cells ( Fig. 3C), it was found that the kinetics of the accumulation of mRNA for nur-77, JunB, and c-fos were very different and quite distinct among the various IEGs.
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Glucose causes transcriptional activation of the nur-77, JunB, and c-fos genes
Accumulation of the mRNAs studied may result from changes in transcription rates and/or mRNA turnover. To assess the first possibility, we directly measured the nur-77, JunB, and c-fos transcription rates using run-on assay with INS-1 cell nuclei. The data in Fig. 4
indicate that the combined presence of high glucose and cpt-cAMP caused a pronounced transcriptional activation of the three genes. The cpt-cAMP-treated cells displayed only a modest effect, whereas high glucose alone did not alter the transcription rate of the three IEGs. The results suggest that the transcriptional activation of these IEGs account for the accumulation of their corresponding transcripts in response to a dual cpt-cAMP and glucose stimulation. Consistent with this view, the half-life of nur-77 mRNA was similar at low (3 mM) and high (15 mM) glucose (data not shown).
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Effect of various nutrient stimuli on IEG induction
We next determined whether the inductive process caused by glucose is specific for this sugar or is mimicked by other nutrient stimuli known to activate Ca2+ signaling and insulin secretion. Mannose, glutamine plus leucine, and pyruvate caused qualitatively similar effects as glucose with respect to nur-77 and c-fos induction ( Fig. 5).
Similar findings were made for JunB (not shown). The action of all tested nutrient stimuli depended on the activation of cAMP signaling. Pyruvate and leucine plus glutamine were two- to threefold more potent than glucose in causing nur-77 and c-fos mRNA accumulation. This is consistent with previous work indicating that these fuel molecules are more potent secretagogues than glucose in INS-1 cells (11). The data are in accordance with the view that ß-cell metabolic activation is implicated in the IEG inductive process caused by glucose and other fuel stimuli.
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GLP-1 and PACAP act as competence factors in glucose-mediated IEG induction
To determine whether the action of cpt-cAMP on IEG induction is mimicked by physiological glucoincretins, we studied the effect of 10 nM GLP-1(7–36 amide) ( Fig. 6A)
and 1 nM PACAP-38 ( Fig. 6B) at low (3 mM) and high (11 mM) glucose. These incretins were tested at concentrations known to be effective (22, 23). In contrast to the IEG inductive process caused by cpt-cAMP at low glucose, GLP-1 or PACAP-38 did not cause an accumulation of c-fos and nur-77 mRNAs at 3 mM glucose. However, in the presence of these incretins, an extremely robust induction of these IEGs was observed at 11 mM glucose. Similar observations were made for the JunB transcript (not shown). Thus, the synergistic nature of the action of glucose with activators of the cAMP pathway is more striking when using physiological glucoincretins than with the pharmacological agent cpt-cAMP. The results also indicate that GLP-1 and PACAP-38 act as competence factors in the action of glucose on the induction of these IEGs. Reciprocally, and unlike the case for cpt-cAMP, elevated glucose acts as a competence factor in the action of these neurohormonal factors.
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Role of cAMP and Ca2+ signaling in IEG induction
GLP-1 binds to an adenylyl-cyclase coupled receptor and increases cAMP in islet tissue (8). Some reports have indicated that GLP-1 also increases cytosolic Ca2+ in pancreatic ß-cells (7) but was not observed in other studies (24). To gain insight into the role of Ca2+ and cAMP in the induction of the studied genes, we measured the intracellular levels of the two messengers in INS-1 cells after glucose and GLP-1 stimulation. Figure 7
shows that high glucose caused a very modest rise in the cAMP content of INS cells. As expected, GLP-1 induced a pronounced elevation in cellular cAMP. The combined presence of GLP-1 and high glucose did not result in a further rise in cAMP. This indicates that the synergistic nature of the two agonists on IEG induction cannot be ascribed to a synergistic elevation of the second messenger cAMP.
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To directly evaluate the role of Ca2+ in the IEG induction process, the action of the two incretins was tested in the absence and presence of the voltage-gated Ca2+ channel inhibitor nifedipine ( Fig. 8).
The results indicate that nifedipine caused a 65% reduction in accumulation of the c-fos and nur-77 transcripts in response to the combined presence of GLP-1 and high glucose, confirming the importance of the glucose-induced Ca2+ rise on IEG activation.
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Finally, we performed intracellular Ca2+ measurements by microfluorometry in indo-1-loaded cells (25). High glucose increased cytosolic Ca2+ concentration in 11 of 14 cells, and GLP-1 at low glucose induced a Ca2+ rise in 5 of 6 cells (data not shown). These observations indicate that GLP-1 activates both cAMP and Ca2+ signaling in INS-1 cells.
Glucose in the presence of cpt-cAMP or GLP-1 also induces IEGs in ßHC9 cells
To confirm our findings made with the rat ß-cell line INS-1 in another system, we chose the mouse HC9 ß-cell line as another relevant model for wild-type pancreatic ß-cells (20). As shown in Fig. 9,
high glucose on its own had no effect on nur-77 and c-fos, whereas glucose amplified by 100% the cAMP-induced transcript accumulation. We also studied the effect of GLP-1 (10 nM) at high and low glucose. The results showed a significant increase of transcript accumulation in the presence of 11 mM glucose, whereas GLP-1 had no effect at low glucose. The Ca2+ channel blocker nifedipine decreased the effect of GLP-1 at high glucose by more than 60%. These results suggest that the activation of IEGs by glucose, cpt-cAMP, and GLP-1 applies to ß-cells in general.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The present study shows that glucose regulates the expression of IEGs in INS-1 ß-cells, particularly c-fos, c-jun, and JunB, which are known to be ‘master switches’ in gene regulation (27). An essential feature of this inductive process is its cAMP dependence, which may explain why this action has been overlooked in previous work. GLP-1, a potent glucoincretin that synergizes with the sugar to enhance insulin release, is a ‘glucose competence’ factor that is known to confer sensitivity to glucose-resistant ß-cells (6). The synergy leading to enhanced IEG expression is striking when the neuropeptides GLP-1 and PACAP-38 are used: receptor-activated and nutrient-stimulated signaling synergize reciprocally to activate IEG transcription. Provided that it may be extended to the in vivo situation, their reciprocal synergistic action is meaningful since both glucose and GLP-1 rise in the blood after oral nutrient ingestion (8).
The dose dependence of IEG mRNA accumulation revealed that glucose is most active at concentrations in the physiological range or slightly above 3–11 mM and somewhat less effective at higher concentrations. This concentration dependency is different from that of insulin secretion, which displays a threshold at 5 mM, a half-maximal effect at around 10 mM, and a maximal action at 16–20 mM (28). Nonetheless, it is similar to the dose dependence of glucose on the biosynthesis of total proteins (29), proinsulin (30), and the converting enzyme PC-3 (31), as well as insulin gene transcription (32) and anaplerosis in purified rat islet ß-cells (33). Thus, it appears that adaptive biosynthetic processes requiring anaplerotic influx of carbons in the citric acid cycle (11) are more sensitive to glucose than exocytosis. The biological significance of this observation is not known, but suggests that the cellular messengers and transduction systems implicated in glucose-regulated exocytosis and long-term adaptive processes are different.
Besides glucose, calorigenic nutrients that are not metabolized in the glycolytic pathway also induced the selected IEGs. This contrasts with the selective action of glucose on a number of metabolic genes, particularly GAPDH (3), L-PK (2), and ACC (1). This suggests that the induction of the studied IEGs c-fos, c-jun, JunB, zif-268, and nur-77 is not implicated in the processes whereby glucose regulates these particular metabolic genes. Consistent with this view, these IEGs do not show CACGTG carbohydrate response elements in their promoter, and the ACC and L-PK promoters have no AP-1 sequences. However, a number of metabolic genes including Glut2 (4) and phosphoenolpyruvate carboxy-kinase (34) contain AP-1 sequences in their regulatory elements. Therefore, it is reasonable to believe that the adaptive response to hyperglycemia involves transcription factors encoded by IEGs, which in turn regulate the expression level of certain metabolic genes that remain to be identified.
What are the transduction pathways that mediate glucose induction of c-fos, c-jun, JunB, zif-268, and nur-77? Glucose only slightly elevates cAMP in INS-1 ß-cell, and the actions of glucose and GLP-1 on the cellular cAMP content are not additive. Thus, additional transduction systems are implicated in the synergistic interaction between the two stimuli. Ca2+ signaling and Ca2+ influx likely play an important role since inhibiting L-type Ca2+ channels with nifedipine markedly reduced IEG transcript accumulation. The c-fos, c-jun, and JunB gene are regulated by the MAP-kinase signaling cascade (35, 36). In addition, glucose and other Ca2+ agonists synergize with cAMP to cause MAP-kinase activation in INS-1 ß-cells (12). It is therefore attractive to hypothesize that MAP-kinase and cAMP signaling mediate the glucose/cAMP effect on IEG transcription. Although not possessing a serum-response element motif, the nur-77 promoter contains sites required to confer Ca2+ and cAMP inducibility. Thus, two RSRF (related to serum response factor) binding sites located in the proximal part of its promoter are responsible for Ca2+ induction of this gene, and several sites contain the 5'CGTCA3' core sequence found in most cAMP response elements (37).
The synergistic and interdependent induction of IEGs by glucose and glucoincretins likely has biological significance, since it concerns the interplay between neuronal and nutrient islet activation. This field is widely studied with regard to obesity and type II diabetes. Three possibilities can be considered that specify the role of the induced IEGs for cell physiology and pathophysiology. 1) The control of cell growth. Since glucose alone promotes INS-1 ß-cell mass expansion (19), it is unlikely that induction of these IEGs per se mediates the action of glucose. The action of GLP-1 on ß-cell growth is unknown, but this hormone would be expected to increase ß-cell proliferation since it increases intracellular cAMP, which is a potent stimulus of ß-cell growth (10). Therefore, the IEGs studied that are known to contribute to mitogenic stimulation in many cells (38) may be implicated in a cell growth amplification phenomenon promoted by the glucoincretins. Finally, the synergistic interdependence of glucose and the glucoincretins GLP-1 and PACAP-38 on IEGs may be a means of exerting a tight control of ß-cell mass. 2) Insulin gene expression. Glucose stimulates proinsulin gene expression at the transcriptional and translational levels; GLP-1 increases the cellular level of proinsulin mRNA and the incorporation of [3H]leucine into proinsulin (9). Consistent with this view, the phorbol ester PMA, which induces c-fos and JunB in various cell types including INS-1 cells (data not shown), stimulates proinsulin transcription in HIT ß-cells (39). Although no AP-1 binding site has been formally identified in the rat insulin promoters, an induction of c-fos and JunB might influence insulin gene expression by another mechanism. Thus, c-Jun has been documented to repress cAMP-induced activity of the human insulin promoter (40). We speculate that increased c-Fos and JunB proteins might sequester c-Jun through dimerization and consequently facilitate glucose/cAMP induction of the insulin gene. 3) ß-cell apoptosis. The concerted induction of the five IEGs considered in our study illustrates the multifactorial control by glucoincretins and glucose of rarely occurring events in ß-cell functions (mitosis, apoptosis). The ß-cell mass has to be controlled by a delicate interplay between cell growth, differentiation, and apoptosis. It is thus not too surprising that c-fos and nur-77, which appear to be implicated in the regulation of apoptosis, are part of the IEG repertory controlled by glucose and glucoincretins.
An important extension of the present findings is the study of glucose effects on IEG induction in tissues other than the endocrine pancreas, as excessive nutrient stimulation has been suggested to play a role in cell proliferation leading to tissue dysplasia and tumor growth (41, 42). Of particular interest is the hypothesis that receptor and nutrient signaling may synergize in many tissues. Indeed, GLP-1 receptors have been detected in lung, exocrine gastric glands, and the human gastric cancer cell line HGT-1 (7).
In conclusion, the results underscore a synergistic interaction between glucose and the two most potent incretins, GLP-1 and PACAP-38, in ß(INS-1) cells in terms of transcriptional activation of IEGs, three of them (c-fos, c-jun, and JunB) being proto-oncogenes coding for widespread transcription factors. Since this is the earliest event in ß-cell activation, the data pinpoint candidate genes that play an important role in long-term phenotypic changes of the ß-cell. Inappropriate expression of these IEGs may lead to ß-cell hyperplasia and uncontrolled cell growth or defective ß-cell adaptation to particular nutritional environments.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Abbreviations: GAPDH, glyceraldehyde 3-phosphate dehydrogenase; ACC, acetyl-CoA carboxylase; L-PK, L-type pyruvate kinase; GLP-1, glucagon-like peptide 1; PACAP-38, pituitary adenylate cyclase-activating polypeptide; IEG, immediate-early response gene; PMA, phorbol 12-myristate 13-acetate; KRB, Krebs-Ringer biocarbonate medium; cpt-cAMP, chlorophenylthio-cyclic AMP; MAP, mitogen-activated protein.
Received for publication July 30, 1997. Accepted for publication March 19, 1998.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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