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Endocrinology Vol. 138, No. 5 1930-1934
Copyright © 1997 by The Endocrine Society

Articles

Regulation of the Rat Proopiomelanocortin Gene Expression in AtT-20 cells. II: Effects of the Pituitary Adenylate Cyclase-Activating Polypeptide and Vasoactive Intestinal Polypeptide

Yoshiaki Aoki, Yasumasa Iwasaki, Masahito Katahira, Yutaka Oiso and Hidehiko Saito

First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya 466, Japan

Address all correspondence and requests for reprints to: Yasumasa Iwasaki, M.D. First Department of Internal Medicine, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466, Japan.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP), members of the glucagon-secretin family, have recently been suggested to be involved in the regulation of corticotropin (ACTH) secretion. In this study, we examined the effects of both peptides on POMC gene expression. Using AtT20PL, a clone of the AtT20 mouse corticotroph tumor cells stably transfected with 0.7 kb of the rat POMC 5' promoter-luciferase fusion gene, the effects of both peptides on the POMC promoter activity were estimated by a luciferase assay. PACAP stimulated POMC 5' promoter activity as well as cAMP generation and ACTH secretion in a dose- and time-dependent manner, with the maximal effect being observed 3 h after the start of incubation. A similar effect was observed with VIP. Although the combined effects of PACAP/CRH or VIP/CRH were greater than that of either hormone alone, no such effect was observed between PACAP and VIP. Furthermore, RT-PCR analysis showed the presence of only the PVR3 receptor subtype in this cell line, which is known to have a similar affinity to PACAP and VIP, indicating that both peptides exert their effects through the same receptor. In contrast to the effect of CRH, which was completely abolished by a protein kinase A inhibitor H89, the effects of PACAP/VIP on POMC expression persisted during H89 treatment, suggesting the involvement of alternative intracellular signaling pathway(s) distinct from the protein kinase A system. Our results suggest that PACAP and VIP have positive effects on POMC gene expression and that multiple signaling pathways are involved in the transcriptional event.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PITUITARY adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide discovered by Miyata et al. (1) and Arimura (2). This peptide has two different forms, a 38-amino acid form, PACAP-38, and a 27-amino acid shorter form, PACAP-27. The first 28 amino acids of PACAP 38 share 68% homology with vasoactive intestinal polypeptide (VIP), and thus it is classified as a member of the glucagon/secretin family (1). In fact, the recently reported PACAP receptor, which consists of three different forms, also shares its functions with the VIP receptor (3, 4). PACAP is distributed in the hypothalamus and other brain areas as well as some peripheral organs (4, 5, 6, 7) and, as its name indicates, PACAP induces cAMP generation in the anterior pituitary cells (1). VIP, originally isolated from the intestine, is also shown to exist in parvocellular neurons in the paraventricular nucleus of the hypothalamus (8). Moreover, receptors of both peptides are found to be expressed in a variety of cellular populations in the anterior pituitary, suggesting the role of PACAP/VIP as a hypophysiotropic factor (9, 10, 11, 12). Nevertheless, physiological roles of PACAP/VIP have not yet been clarified. This may partly be due to the relatively weak actions of the peptides as a releasing factor, or to the lack of evidence supporting the direct action of the peptides for the pituitary hormone-secreting cells. In fact, in the case of PACAP, some data suggest that PACAP may exert its action indirectly by acting through the folliculostellate cells (13). However, direct actions of PACAPs on corticotroph, gonadotroph, or somatotroph have recently been demonstrated using clonal pituitary tumor cell lines (14, 15, 16, 17, 18).

In the companion paper (19), we established AtT20PL, a clonal cell line derived from the AtT20/D16v mouse corticotroph tumor cells, in which the rat POMC 5' promoter-luciferase fusion gene was stably transfected. Using this cell line, cultured with low serum medium, we were able to delineate efficiently the dynamics of transcriptional activity of the POMC promoter by various secretagogues. Because of the homogeneous nature of the cells, it is a suitable model to study the direct effects of PACAP/VIP on corticotroph and their underlying intracellular signal transduction mechanism(s).

In this study, we showed the positive effects of PACAP/VIP on POMC gene expression as well as ACTH secretion. We also identified the receptor subtype responsible for the action of both peptides. Furthermore, we found that not only cAMP/protein kinase A (PKA) but also some other signaling pathway(s) is responsible for the positive regulation of POMC gene expression.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Materials
Rat CRH, PACAP-38, and VIP were obtained from Peptide Institute (Osaka, Japan). 3-isobutyl-1-methylxanthine (IBMX) was from Sigma (St. Louis, MO). N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89) was from Seikagaku Kogyo (Tokyo, Japan).

Experiments
AtT20PL, a clone of AtT20/D16v mouse corticotroph tumor cells stably transfected with approximately 0.7 kb of the rat POMC 5' promoter-luciferase fusion gene, described in detail in the companion paper (19), was used in this study.

For all the experiments, AtT20PL cells were cultured with low serum medium (DMEM supplemented with 1% FBS) for 4 days, as described (19). On the day of the experiment, a 0.1% volume of the solutions for each test reagent, in 1000x concentration, or solvent alone, was added directly into the culture media of each dish, and the cells were incubated for the defined time interval. All the reagents were dissolved in sterile double distilled water except CRH, which was dissolved in sterile 0.1% acetic acid solution. At the end of incubation, the culture media were removed, and the cells were harvested for the luciferase assay. In the experiments in which ACTH secretion and cAMP generation were studied, cells were preincubated with IBMX (200 µM) 30 min before the addition of the test reagents, and then the culture media were changed to the serum-free media with the test reagent(s) and IBMX at the start of the experiment. After the cells were incubated for the defined time interval, culture media were collected for ACTH and cAMP assay.

RT-PCR procedure
RNA was isolated from the AtT20PL cells using TRIzol reagent (Life Technologies, Grand Islands, NY), and 1.8 µg of the total RNA was used for the reverse transcription reaction with avian myeloblastosis virus reverse transcriptase (Takara Shuzo, Ohtsu, Japan). The cDNA obtained was then amplified by PCR with Taq DNA polymerase (Takara Shuzo) using the specific primer set for each subtype of the PACAP/VIP receptor cDNA as previously described (18).

Measurements
Luciferase assay was performed as described (19). ACTH in culture media were measured by radioimmunometric assay (ACTH IRMA-kit, Mitsubishi Chemical, Tokyo, Japan). cAMP in culture media were determined by RIA (Yamasa Shoyu, Tokyo, Japan).

Data analyses
Samples in each group of the experiments were in triplicate or quadruplicate. All data were expressed as mean ± SE. When statistical analyses were performed, data were compared by one-way ANOVA with Duncan’s multiple range test, and P values below 0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The effect of forskolin on POMC gene expression
We first examined the effect of forskolin, an activator of adenylate cyclase, on the POMC 5' promoter activity to confirm that the cAMP/PKA pathway is the positive regulator of the gene. As shown in Fig. 1Go, A and B, forskolin potently stimulated POMC gene expression in a dose- and time-related manner. Time-course study showed that the maximal effect was observed 4–5 h after the stimulation, with a 5-fold increase compared with the basal value. Dose-response study showed significant effects at and above 10 µM. These results confirm that cAMP is one of the major second messengers for the positive regulation of POMC gene expression.



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  		Figure 1. The time course (A) and dose response (B) effects of forskolin on the POMC 5' promoter activity in AtT20PL cells. A, Cells were treated with forskolin (10 µM) for 0 to 6 h. B, Cells were treated with forskolin (10 nM to 100 µM) for 3 h. Each value is shown as a percentage of the basal value. Fsk, forskolin; *, P < 0.05 vs. basal value.

 
The effect of PACAP on POMC gene expression
We then examined the effect of PACAP on the POMC 5' promoter activity. As shown in Fig. 2Go, A and B, PACAP-38 stimulated POMC gene expression in a time- and dose-related manner. Time course study showed that the maximal effect was observed 3–4 h after the stimulation, with 40% increase compared with the basal value. Dose-response study showed a significant effect at and above 100 pM, and no additional effect was observed above 100 nM. These results indicate that PACAP has an acute, stimulatory effect on POMC gene expression at the transcriptional level, although the degree of stimulation was much weaker than that of CRH (see Fig. 4Go) (19).



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  		Figure 2. The time course (A) and dose response (B) effects of PACAP on the POMC 5' promoter activity in AtT20PL cells. A, Cells were treated with PACAP (100 nM) for 0–6 h. B, Cells were treated with PACAP (10 pM to 1 µM) for 3 h. Each value is shown as a percentage of the basal value. *, P < 0.05 vs. basal value.

 


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  		Figure 4. The combined effects of CRH/PACAP (A), CRH/VIP (B), or PACAP/VIP (C) on cAMP efflux, ACTH secretion and the POMC 5' promoter activity in AtT20PL cells. A, Cells were treated with CRH (100 nM) and/or PACAP (100 nM) for 3 h. B, Cells were treated with CRH (100 nM) and/or VIP (100 nM) for 3 h. C, Cells were treated with PACAP (100 nM) and/or VIP (100 nM) for 3 h. At the end of each experiment, culture media were collected for cAMP and ACTH assays. *, P < 0.05 vs. control croup; +, P < 0.05 vs. CRH group (A, B) or PACAP group (C). C, Control; P, PACAP.

 
The effect of VIP on POMC gene expression
We also examined the effect of VIP on the POMC 5' promoter activity. As shown in Fig. 3Go, A and B, VIP had a positive effect on POMC gene expression. Time-course study showed that the maximal effect was observed 3 h after the stimulation, with a 40–50% increase compared with the basal value. Dose-response study showed a significant effect at and above 1 nM, and no additional effect was observed above 100 nM. These results, which are very similar to those of PACAP, suggest that VIP and PACAP are acting via the same mechanism.



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  		Figure 3. The time course (A) and dose response (B) effects of VIP on the POMC 5' promoter activity in AtT20PL cells. A, Cells were treated with VIP (100 nM) for 0–6 h. B, Cells were treated with VIP (10 pM to 1 µM) for 3 h. Each value is shown as a percentage of the basal value. *, P < 0.05 vs. basal value.

 
The combined effects of CRH, PACAP, and VIP on cAMP efflux, ACTH secretion, and POMC gene expression
We then examined the combined effects of CRH/PACAP, CRH/VIP, or PACAP/VIP on cAMP generation and ACTH secretion as well as the POMC 5' promoter activity. As shown in Fig. 4Go, A and B, PACAP-38 (100 nM) and VIP (100 nM) caused significant increase in cAMP efflux, ACTH secretion, and POMC expression, although much less potently than CRH (100 nM) in all parameters. When these maximally effective doses of CRH and PACAP-38, or CRH and VIP were simultaneously applied, values were significantly higher in all parameters than those of CRH alone. In contrast, no additional effect was observed between PACAP-38 and VIP in any of the parameters (Fig. 4CGo), suggesting again that both hormones are sharing the receptor and/or signal transduction mechanism.

RT-PCR analysis of the PACAP/VIP receptor subtypes in AtT20PL cells
To identify the subtype(s) of the PACAP/VIP receptor expressed in AtT20PL cells, RT-PCR analysis was carried out using the sets of primers specific for the three receptor subtypes (18). As shown in Fig. 5Go, primers specific for PVR3 produced a band of the predicted size (325 bp). In contrast, no PCR products corresponding to PVR1 (280, 364, or 448 bp) or PVR2 (299 bp) were detected. The result suggests that AtT20PL cells express only PVR3, and that the effects of PACAP/VIP are mediated through the receptor subtype.



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  		Figure 5. Expression of the PACAP/VIP receptor subtypes analyzed by RT-PCR in AtT20PL cells. The figure shows photographs of the ethidium bromide-stained products using agarose gel electrophoresis. cDNA produced from an RT reaction using total RNA from AtT20PL cells was amplified using PCR with pairs of oligonucleotide primers specific for PVR1, PVR2, or PVR3 (18). Only a DNA fragment of PVR3 with the predicted length (325 bp) was amplified.

 
The effects of PKA inhibitor H89 on PACAP/VIP-induced POMC gene expression
Finally, we examined the effects of H89, a specific inhibitor of PKA, on PACAP/VIP-stimulated POMC 5' promoter activity, to examine the role of cAMP/PKA pathway in the effects of both peptides. As shown in Fig. 6Go, PACAP-38 and VIP, as well as CRH, significantly stimulated POMC gene expression, in agreement with the experiments shown above. The effect of CRH was completely abolished under the treatment with H89 (19). In contrast, the positive effects of PACAP-38 and VIP still persisted during H89 treatment. These results suggest that, unlike CRH, alternative cAMP/PKA-independent pathway(s) is/are also involved in the positive effects of PACAP and VIP on POMC gene expression.



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  		Figure 6. The effects of PKA inhibitor H89 on the CRH-, PACAP-, or VIP-induced POMC 5' promoter activity in AtT20PL cells. Cells were pretreated for 30 min with H89 (30 µM), and then treated with CRH (left) (100 nM, 3 h), PACAP (middle) (100 nM, 3 h), or VIP (right) (100 nM, 3 h) as well as H89. Dotted bars represent control groups, whereas closed bars represent hormone-treated groups. Each value is shown as a percentage of the control value. *, P < 0.05 vs. control.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, using AtT20PL murine corticotroph tumor cells, we showed that PACAP and VIP have acute, stimulatory effects on POMC gene expression as well as ACTH secretion. RT-PCR analysis indicates that both hormones act through the PVR3 receptor subtype, which is known to have equal affinities to PACAP and to VIP (18, 20, 21). Furthermore, the data using PKA inhibitor suggest that an alternative signaling pathway(s) besides cAMP/PKA system is involved in transducing PACAP/VIP-induced intracellular signals to the POMC gene, in contrast to CRH, which is supposed to be mediated only through PKA.

Our results demonstrate that PACAP (above 100 pM) acutely stimulates cAMP generation, ACTH secretion, and POMC 5' promoter activity, in agreement with the recent report by Boutillier (17). We also found for the first time that VIP (above 1 nM) has a similar effect on POMC gene expression. These data suggest that PACAP/VIP may be a positive regulator of ACTH/POMC expression, although the effects are less potent than CRH or catecholamines obtained under the same experimental conditions (19). Our data also show that the combined effects of maximally effective doses of CRH/PACAP or CRH/VIP are greater in all parameters than the effects of either hormone alone, indicating that PACAP/VIP and CRH act through different receptors, although all hormones are known to activate the adenylate cyclase/cAMP pathway. On the other hand, no additional effect is observed when PACAP and VIP are used simultaneously, and the effects of PACAP and VIP observed are very similar both in the time-course and dose-response profile. Based on these results, we assume that PACAP and VIP are acting through the same receptor.

To clarify the issue more precisely, we tried to identify the PACAP/VIP receptor subtype involved. Recent molecular analyses of PACAP/VIP receptor genes revealed at least three different subtypes of the receptor: PVR1, 2, and 3 (3, 4, 18, 20, 21). Whereas PVR1 has preferential affinity for PACAP over VIP, and are coupled with adenylate cyclase (corresponding to the type I binding site), PVR2 and PVR3 have similar affinities for both hormones (corresponding to the type II binding site). When the expression of the three known receptor subtypes were analyzed by RT-PCR (18), expression of only PVR3 was observed in AtT20PL cells. This is in accordance with our data discussed above, indicating that PACAP and VIP act through the same receptor subtype, i.e. PVR3. The results also suggest that the effects of PACAP/VIP are at least partly mediated through the cAMP/PKA pathway because PVR3 is known to be coupled with adenylate cyclase (18, 20, 21). In fact, our data show that both hormones stimulate cAMP generation as well as ACTH secretion and POMC expression, and forskolin, an activator of adenylate cyclase, is shown to be a potent stimulator of the transcription of the gene as well.

A previous study showed that the effects of PACAP/VIP on the POMC gene were completely eliminated by a dominant inhibitory mutant of PKA (17). Our results, however, demonstrate that PACAP/VIP could still stimulate the POMC 5' promoter activity under the treatment of H89, a specific inhibitor of PKA (22). This does not seem to be due to incomplete suppression of the enzyme by H89 because the effects of CRH or catecholamines, more potent stimulators of POMC expression through the cAMP/PKA pathway, were completely abolished under the same experimental conditions (19). Because the PVR3 receptor is suggested to be coupled with phospholipase C as well (21), we assume that an alternative signaling pathway(s) other than the cAMP/PKA system, probably a Ca2+-mediated one, is/are also involved in the effect of PACAP/VIP on POMC gene expression. We are currently trying to identify this PKA-independent pathway(s) to completely elucidate the intracellular signaling system of PACAP/VIP.

PACAP has been shown to exist in the median eminence by immunohistochemical studies (5, 6). VIP is distributed in the hypothalamus (23, 24) and is known to be released from the hypothalamus through the hypophyseal portal vein (25). It also appears to be released from the lactotroph of the anterior pituitary in a paracrine fashion (26, 27). Although a part of the effects of PACAP/VIP may be mediated via folliculostellate cells that have PACAP receptors (13), it has been shown that some populations of the corticotroph cells possess a binding capacity for PACAP/VIP (9), suggesting a direct effect of the hormones on ACTH synthesis/secretion. Furthermore, as shown in a recent study, PACAP may have a differentiating effect on corticotroph cells (16). Further examinations, especially in vivo, will clarify the physiological role of PACAP/VIP as regulators of the hypothalamo-pituitary-adrenal axis.


   Acknowledgments
 
We are indebted to Dr. Malcolm Low for providing the rat POMC gene and to Dr. Keiichi Itoi for his helpful discussions.

Received October 14, 1996.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Miyata A, Arimura A, Dahl RR, Minamino N, Uehara A, Jiang L, Culler MD, Coy DH 1989 Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun 164:567–574[CrossRef][Medline]
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  6. Gottschall PE, Tatsuno I, Miyata A, Arimura A 1990 Characterization and distribution of binding sites for the hypothalamic peptide, pituitary adenylate cyclase-activating polypeptide. Endocrinology 127:272–277[Abstract]
  7. Köves K, Arimura A, Görcs TG, Somogyvári-Vigh A 1991 Comparative distribution of immunoreactive pituitary adenylate cyclase activating polypeptide and vasoactive intestinal polypeptide in rat forebrain. Neuroendocrinology 54:159–169[Medline]
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  9. Vigh S, Arimura A, Gottschall PE, Kitada C, Somogyvári-Vigh A, Childs GV 1993 Cytochemical characterization of anterior pituitary target cells for the neuropeptide, pituitary adenylate cyclase activating polypeptide (PACAP), using biotinylated ligands. Peptide 14:59–65[CrossRef][Medline]
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  11. Culler MD, Paschall CS 1991 Pituitary adenylate cyclase-activating polypeptide (PACAP) potentiates the gonadotropin-releasing activity of luteinizing hormone-releasing hormone. Endocrinology 129:2260–62[Abstract]
  12. Koch B, Lutz-Bucher B 1993 Vasopressin, unlike phorbol ester, fails to synergically interact with pituitary adenylate cyclase activating polypeptide (PACAP) in stimulating cyclic AMP formation and ACTH secretion in cultured anterior pituitary cells. Mol Cell Endocrinol 92:175–181[CrossRef][Medline]
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  14. Propato-Mussafiri R, Kanse SM, Ghatei MA, Bloom SR 1992 Pituitary adenylate cyclase-activating polypeptide releases 7B2, adrenocorticotrophin, growth hormone and prolactin from the mouse and rat clonal pituitary cell line AtT-20 and GH3. J Endocrinol 132:107–113[Abstract]
  15. Koch B, Lutz-Bucher B 1992 Pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates cyclic AMP formation as well as peptide output of cultured pituitary melanotroph and AtT-20 corticotrophs. Regul Pept 38:45–53[CrossRef][Medline]
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  17. Boutillier AL, Monnier D, Koch B, Loeffler JP 1994 Pituitary adenylate cyclase-activating peptide: a hypophysiotropic factor that stimulate proopiomelanocortin gene transcription, and proopiomelanocortin-derived peptide secretion in corticotrophic cells. Neuroendocrinology 60:493–502[Medline]
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  19. Aoki Y, Iwasaki Y, Katahira M, Oiso Y, Saito H 1997 Regulation of the rat proopiomelanocortin gene expression in AtT-20 cells. I: Effects of the common secretagogues. Endocrinology 138:1923–1929[Abstract/Free Full Text]
  20. Lutz EM, Sheward WJ, West KM, Morrow JA, Fink G, Harmer AJ 1993 The VIP2 receptor: molecular characterization of a cDNA encoding a novel receptor for vasoactive intestinal peptides. FEBS Lett 334:3–8[CrossRef][Medline]
  21. Inagaki N, Yoshida H, Mizuta M, Mizuno N, Fujii Y, Gonoi T, Miyazaki J-I, Seino S 1994 Cloning and functional characterization of a third pituitary adenylate cyclase-activating polypeptide receptor subtype expressed in insulin-secreting cells. Proc Natl Acad Sci USA 91:2679–2683[Abstract/Free Full Text]
  22. Chijiwa T, Mishima A, Hagiwara M, Sano M, Hayashi K, Inoue T, Naito K, Toshioka T, Hidaka H 1990 Inhibition of forskolin-induced neurite outgrowth and protein phosphorylation by a newly synthesized selective inhibitor of cyclic AMP-dependent protein kinase, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline sulfonamide (H-89), of PC12D pheochromocytoma cells. J Biol Chem 265:5267–5272[Abstract/Free Full Text]
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Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: From Structure to Functions
Pharmacol. Rev., June 1, 2000; 52(2): 269 - 324.
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 J. Biol. Chem.Home page
M. Delgado and D. Ganea
Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-activating Polypeptide Inhibit Interleukin-12 Transcription by Regulating Nuclear Factor kappa B and Ets Activation
J. Biol. Chem., November 5, 1999; 274(45): 31930 - 31940.
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 J. Immunol.Home page
M. Delgado, E. J. Munoz-Elias, R. P. Gomariz, and D. Ganea
Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-Activating Polypeptide Enhance IL-10 Production by Murine Macrophages: In Vitro and In Vivo Studies
J. Immunol., February 1, 1999; 162(3): 1707 - 1716.
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M. Delgado, E. J. Munoz-Elias, Y. Kan, I. Gozes, M. Fridkin, D. E. Brenneman, R. P. Gomariz, and D. Ganea
Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-activating Polypeptide Inhibit Tumor Necrosis Factor alpha  Transcriptional Activation by Regulating Nuclear Factor-kB and cAMP Response Element-binding Protein/c-Jun
J. Biol. Chem., November 20, 1998; 273(47): 31427 - 31436.
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