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PubMed1995

Mutational analysis of the insulin-like growth factor I prohormone processing site.

Insulin-like growth factor I (IGF-I) is a mitogenic peptide that is produced in most tissues and cell lines and plays an important role in embryonic development and postnatal growth. IGF-I is initially synthesized as a prohormone precursor that is converted to mature IGF-I by endoproteolytic removal of the carboxyl-terminal E-domain. Regulation of the conversion of proIGF-I to mature IGF-I is a potential mechanism by which the biological activity of this growth factor might be modulated. Endoproteolysis of the IGF-I prohormone occurs at the unique pentabasic motif Lys-X-X-Lys-X-X-Arg71-X-X-Arg-X-X-Arg. Recently, a family of enzymes which cleave prohormone precursors at sites containing multiple basic residues has been discovered. The goals of this study were 1) to determine which basic residues in the pentabasic proIGF-I processing site were necessary for proper cleavage and 2) to examine the role that subtilisin-related proprotein convertase 1 (SPC1/furin) might play in proIGF-I processing. We have shown that an expression vector coding for an epitope-tagged proIGF-I directs synthesis and secretion of mature IGF-I-(1-70), extended IGF-I-(1-76), proIGF-I, and N-glycosylated proIGF-I in human embryonic kidney 293 cells. Extended IGF-I-(1-76) is produced by cleavage at Arg77 and requires both Arg74 (P4) and Arg77 (P1). Cleavage at Arg77 does not occur in the SPC1-deficient cell lines RPE.40 and LoVo, suggesting that processing at this site is mediated by SPC1. Mature IGF-I-(1-70) is produced by cleavage at Arg71 and requires both Lys68 (P4) and Arg71 (P1). Lys65 in the P7 position is important for efficient cleavage. SPC1 is not required for processing at Arg71 since this cleavage occurs in RPE.40 and LoVo cells. These data suggest the existence of a processing enzyme which is specific for the Lys-X-X-Arg motif of proIGF-I.

Amino Acid Sequence↗

PubMed1992

Proinsulin processing by the subtilisin-related proprotein convertases furin, PC2, and PC3.

Experiments using recombinant vaccinia viruses expressing rat proinsulin I coinfected into COS-7 cells with recombinant vaccinia virus expressing human furin, human PC2, mouse PC3 (subtilisin-related proprotein convertases 1-3, respectively), or yeast Kex2 indicate that in this system both Kex2 and furin produce mature insulin, whereas PC2 selectively cleaves proinsulin at the C-peptide-A-chain junction. This is a property consistent with its probable identity with the rat insulinoma granule type II proinsulin processing activity as described by Davidson et al. [Davidson, H. W., Rhodes, C. J. & Hutton, J. C. (1988) Nature (London) 333, 93-96]. PC3 generates mature insulin but cleaves preferentially at the proinsulin B-chain-C-peptide junction. This pattern of cleavage by PC3 is similar, but not identical, to that of the highly B-chain-C-peptide junction-selective type I activity as described by Davidson et al., perhaps due to the presence of a P4 arginine residue near the C-peptide-A-chain junction unique to the rat proinsulins. These results along with data presented on the expression of both PC2 and PC3 in islet beta cells strongly support the conclusion that these proteases are involved in the conversion of proinsulin to insulin in vivo.

Amino Acid Sequence↗

PubMed2004

Monitoring for dynamic biological processing by intramolecular bioluminescence resonance energy transfer system using secreted luciferase.

Proteolytic processing plays crucial roles in physiological and pathophysiological cellular functions such as peptide generation, cell cycle, and apoptosis. We developed a novel biophysical bioluminescence resonance energy transfer (BRET) system between a secreted Vargula luciferase (Vluc) and an enhanced yellow fluorescent protein (EYFP) for visualization of cell biological processes. The bioluminescence spectrum of the fusion protein (Vluc-EYFP) is bimodal (lambdamax = 460 nm (Vluc) and 525nm (EYFP)), indicating that the excited-state energy of Vluc transfers to EYFP (in short, BRET). The BRET signal can be measured in the culture medium and pursue quantitative production of two neuropeptides, nocistatin (NST) and nociceptin/orphanin FQ (N/OFQ) in living cells. NST and N/OFQ are located in tandem on the same precursor, but NST exhibits antagonistic action against N/OFQ-induced central functions. Insertion of a portion of the NST-N/OFQ precursor (Glu-Gln-Lys-Gln-Leu-Gln-Lys-Arg-Phe-Gly-Gly-Phe-Tyr-Gly) in Vluc-EYFP makes the fusion protein cleavable at Lys-Arg in NG108-15 cells, and proprotein convertase 1 enhances this digestion. The change in BRET signals quantifies the processing of the fusion protein. Our novel intramolecular BRET system using a secreted luciferase is useful for investigating peptide processing in living cells.

Bacterial Proteins↗

PubMed2007

Regulation of pancreatic endocrine cell differentiation by sulphated proteoglycans.

AIMS/HYPOTHESIS: Epithelium-mesenchyme interactions play a major role in pancreas development. Recently, we demonstrated that embryonic pancreatic mesenchyme enhanced progenitor cell proliferation but inhibited endocrine cell differentiation. Here, we investigated the role played by sulphated proteoglycans, which are known to be essential to embryonic development, in this inhibitory effect. MATERIALS AND METHODS: We first determined the expression of the genes encoding glypicans, syndecans and the main glycosaminoglycan chain-modifying enzymes in immature embryonic day (E) 13.5 and more differentiated E17.5 rat pancreases. Next, using an in vitro model of pancreas development, we blocked the action of endogenous sulphated proteoglycans by treating embryonic pancreases in culture with chlorate, an inhibitor of proteoglycan sulphation, and examined the effects on pancreatic endocrine cell differentiation. RESULTS: We first showed that expression of the genes encoding glypicans 1, 2, 3 and 5 and heparan sulphate 2-sulfotransferase decreased between E13.5 and E17.5. We next found that alteration of proteoglycan action by chlorate blocked the inhibitory effect of the mesenchyme on endocrine differentiation. Chlorate-treated pancreases exhibited a dramatic increase in beta cell number in a dose-dependent manner (169-and 375-fold increase with 30 mmol/l and 40 mmol/l chlorate, respectively) and in alpha cell development. Insulin-positive cells that developed in the presence of chlorate exhibited a phenotype of mature cells with regard to the expression of the following genes: pancreatic and duodenal homeobox gene 1 (Pdx1), proprotein convertase subtilisin/kexin type 1 (Pcsk1; previously known as pro-hormone convertase 1/3), proprotein convertase subtilisin/kexin type 2 (Pcsk2; previously known as pro-hormone convertase 2) and solute carrier family 2 (facilitated glucose transporter), member 2 (Slc2a1; previously known as glucose transporter 2). Finally, we showed that chlorate activated endocrine cell development by inducing neurogenin 3 (Neurog3) expression in early endocrine progenitor cells. CONCLUSIONS/INTERPRETATION: We demonstrated that sulphated proteoglycans control pancreatic endocrine cell differentiation. Understanding the mechanism by which sulphated proteoglycans affect beta cell development could be useful in the generation of beta cells from embryonic stem cells.

Animals↗

PubMed1998

Proglucagon processing in an islet cell line: effects of PC1 overexpression and PC2 depletion.

Proglucagon (proG) is differentially processed in the A cells of the pancreas to yield glucagon, and in the L cells of the intestine to generate glicentin, oxyntomodulin, the incretin glucagon-like peptide (GLP)-1(7-36NH2) and the intestinotropin GLP-2. To establish roles for the prohormone convertases PC1 and PC2 in proG processing within the context of a physiological model, we created stable cell lines from an islet-derived cell line, InR1-G9. These cells express proG and PC2, but not PC1, messenger RNA (mRNA). InR1-G9 cells were stably transfected with PC1 or antisense PC2. Selection was carried out in G418 (InR1-G9/PC1) or Zeocin (InR1-G9/ASPC2). Both PC1 mRNA and protein were highly expressed in InR1-G9/PC1 cells (P < 0.01-0.001) compared with wild-type (WT) cells. Cells transfected with ASPC2 demonstrated significant decreases in both PC2 mRNA (P < 0.001) and protein (P < 0.05) levels. ProG-derived peptides in WT, control, InR1-G9/PC1, and InR1-G9/ASPC2 cells were identified by HPLC and RIA. Overexpression of PC1 in InR1-G9 cells resulted in increased processing to glicentin (P < 0.01), oxyntomodulin (P < 0.05), and GLP-2 (P < 0.05). Interestingly, processing to GLP-1(7-36NH2) did not increase upon transfection of PC1. Transfection of InR1-G9 cells with ASPC2 resulted in the disappearance of glicentin (P < 0.05). However, production of glucagon was not altered by antisense deletion of PC2. Surprisingly, GLP-1(7-36NH2) production appeared to be augmented (P < 0.05) in InR1-G9/ASPC2 cells, whereas GLP-2 production was not altered. In conclusion, these studies establish the role of PC1 in the processing of proG to the intestinal proG-derived peptides. This study also establishes a role for PC2 in the production of glicentin; however, the liberation of glucagon appears to be mediated by another, yet to be identified, convertase.

Animals↗

PubMed2005

Cholecystokinin levels in prohormone convertase 2 knock-out mouse brain regions reveal a complex phenotype of region-specific alterations.

Prohormone convertase 2 is widely co-localized with cholecystokinin in rodent brain. To examine its role in cholecystokinin processing, cholecystokinin levels were measured in dissected brain regions from prohormone convertase 2 knock-out mice. Cholecystokinin levels were lower in hippocampus, septum, thalamus, mesencephalon, and pons in knock-out mice than wild-type mice. In cerebral cortex, cortex-related structures and olfactory bulb, cholecystokinin levels were higher than wild type. Female mice were more affected by the loss of prohormone convertase 2 than male mice. The decrease in cholecystokinin levels in these brain regions shows that prohormone convertase 2 is important for cholecystokinin processing. Quantitative polymerase chain reaction measurements were performed to examine the relationship between peptide levels and cholecystokinin and enzyme expression. They revealed that cholecystokinin and prohormone convertase 1 mRNA levels in cerebral cortex and olfactory bulb were actually lower in knock-out than wild type, whereas their expression in other brain regions of knock-out mouse brain was the same as wild type. Female mice frequently had higher expression of cholecystokinin and prohormone convertase 1, 2, and 5 mRNA than male mice. The loss of prohormone convertase 2 alters CCK processing in specific brain regions. This loss also appears to trigger compensatory mechanisms in cerebral cortex and olfactory bulb that produce elevated levels of cholecystokinin but do not involve increased expression of cholecystokinin, prohormone convertase 1 or 5 mRNA.

Amino Acid Sequence↗

PubMed2002

Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects.

The subtilisin-like proprotein convertases PC1/3 (SPC3) and PC2 (SPC2) are believed to be the major endoproteolytic processing enzymes of the regulated secretory pathway. They are expressed together or separately in neuroendocrine cells throughout the brain and dispersed endocrine system in both vertebrates and invertebrates. Disruption of the gene-encoding mouse PC1/3 has now been accomplished and results in a syndrome of severe postnatal growth impairment and multiple defects in processing many hormone precursors, including hypothalamic growth hormone-releasing hormone (GHRH), pituitary proopiomelanocortin to adrenocorticotropic hormone, islet proinsulin to insulin and intestinal proglucagon to glucagon-like peptide-1 and -2. Mice lacking PC1/3 are normal at birth, but fail to grow normally and are about 60% of normal size at 10 weeks. They lack mature GHRH, have low pituitary growth hormone (GH) and hepatic insulin-like growth factor-1 mRNA levels and resemble phenotypically the "little" mouse (Gaylinn, B. D., Dealmeida, V. I., Lyons, C. E., Jr., Wu, K. C., Mayo, K. E. & Thorner, M. O. (1999) Endocrinology 140, 5066-5074) that has a mutant GHRH receptor. Despite a severe defect in pituitary proopiomelanocortin processing to mature adrenocorticotropic hormone, blood corticosterone levels are essentially normal. There is marked hyperproinsulinemia but without impairment of glucose tolerance. In contrast, PC2-null mice lack mature glucagon and are chronically hypoglycemic (Furuta, M., Yano, H., Zhou, A., Rouille, Y., Holst, J., Carroll, R., Ravazzola, M., Orci, L., Furuta, H. & Steiner, D. (1997) Proc. Natl. Acad. Sci. USA 94, 6646-6651). The PC1/3-null mice differ from a human subject reported with compound heterozygosity for defects in this gene, who was of normal stature but markedly obese from early life. The PC1/3-null mice are not obese. The basis for these phenotypic differences is an interesting topic for further study. These findings prove the importance of PC1/3 as a key neuroendocrine convertase.

Adrenocorticotropic Hormone↗

PubMed2004

The melanocortin receptor subtypes in chicken have high preference to ACTH-derived peptides.

1 Melanocortin (MC) receptors are widely distributed throughout the body of chicken, like in mammals, and participate in a wide range of physiological functions. 2 To clarify the pharmacological impact of ligands acting in the MC system, we expressed the chicken MC1, MC2, MC3, MC4 and MC5 (cMC1-5) receptors in eukaryotic cells and performed comprehensive pharmacological characterization of the potency of endogenous and synthetic melanocortin peptides. 3 Remarkably, the cMC receptors displayed high affinity for ACTH-derived peptides and in general low affinity for alpha-MSH. It is evident that not only the cMC2 receptor but also the other cMC receptors interact with ACTH-derived peptide through an epitope beyond the sequence of alpha-MSH. 4 The synthetic ligand MTII was found to be a potent agonist whereas HS024 was a potent antagonist at the cMC4 receptor, indicating that these ligands are suitable for physiological studies in chicken. 5 We also show the presence of prohormone convertase 1 (PC1) and PC2 genes in chicken, and that these peptides are coexpressed with proopiomelanocortin (POMC) in various tissues.

Adrenocorticotropic Hormone↗

PubMed1991

Isolation and functional expression of a mammalian prohormone processing enzyme, murine prohormone convertase 1.

We have combined gene cloning with an assay for prohormone biosynthesis and processing in Xenopus oocytes to identify the genes that encode mammalian prohormone processing enzymes. The coinjection of RNA encoding murine prohormone convertase 1 (mPC1), a mammalian endoprotease, along with proopiomelanocortin RNA into an oocyte results in the appropriate cleavage after paired basic residues in the proopiomelanocortin polyprotein necessary to generate corticotropin. The ability of mPC1 to generate corticotropin, along with the observation that mPC1 is specifically expressed in endocrine and neuronal cells, suggests that the mPC1 gene encodes the endopeptidase responsible for the pathway of proopiomelanocortin cleavage observed in the anterior pituitary.

Amino Acid Sequence↗

PubMed2005

Cytokines affect PDX-1 expression, insulin and proinsulin secretion from iNOS deficient murine islets.

In rodent islets, exposure to interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma) induces expression of inducible nitric oxide synthase (iNOS) and subsequent nitric oxide (NO) formation, which may inhibit islet function. However, cytokines may also induce NO-independent islet suppression. The present aim was to investigate the effect of cytokine exposure to iNOS deficient (iNOS-/-) mouse islets on various islet functions. Islets from iNOS-/- and wt mice exposed to IL-1beta or (IL-1beta + IFN-gamma) for 2-20 h showed different kinetics of glucose-stimulated insulin secretion. In iNOS-/- islets, IL-1beta at high glucose induced a delayed and prolonged stimulation of insulin secretion, and this was followed by an increase in phospholipase D mRNA expression. After 6 and 24 h, proinsulin convertase 1 and 2 (PC1 and PC2) mRNA expression was suppressed and proinsulin secretion increased from wt islets. In iNOS-/- islets, PC1 expression was recovered after 24 h, and there was no difference in proinsulin secretion. PDX-1 mRNA expression was suppressed independent of NO-formation. We conclude that cytokines induce both NO-dependent and NO-independent functional inhibition of murine beta-cells.

Animals↗

PubMed2005

Recombinant prohormone convertase 1 and 2 cleave purified pro cholecystokinin (CCK) and a synthetic peptide containing CCK 8 Gly Arg Arg and the carboxyl-terminal flanking peptide.

Purified recombinant prohormone convertase 1 and 2 (PC1 and PC2) cleave a peptide containing cholecystokinin (CCK) 8 Gly Arg Arg and the carboxyl-terminal peptide liberating CCK 8 Gly Arg Arg. PC1 and PC2 also cleave purified pro CCK, liberating the amino terminal pro-peptide while no carboxyl-terminal cleavage was detected. Under the conditions of the in vitro cleavage assay, it appears that the carboxyl-terminal cleavage site of pro CCK is not accessible to the enzymes while this site is readily cleaved in a synthetic peptide. Additional cellular proteins that unfold the prohormone may be required to expose the carboxyl-terminal site for cleavage.

Animals↗

PubMed2000

The C-terminal region of proSAAS is a potent inhibitor of prohormone convertase 1.

ProSAAS is a recently discovered 26-kDa neuroendocrine protein that was previously found to inhibit prohormone convertase (PC) 1 and not PC2. In the present study, the specificity of proSAAS toward other members of the prohormone convertase family was determined. Two microm proSAAS selectively inhibits PC1 but not furin, PACE4, PC5A, or PC7. The PC1 inhibitory region of proSAAS was mapped to an 8-12-residue region near the C terminus that includes a critical Lys-Arg sequence. Synthetic peptides corresponding to this region are competitive inhibitors of PC1 with apparent K(i) values of 14-40 nm. The inhibition becomes more effective with incubation time, indicating that the inhibitor is slow binding. A fusion protein containing the inhibitory region of proSAAS linked to the C terminus of glutathione S-transferase binds the 71-kDa form but not the 85-kDa form of PC1. This binding, which occurs at pH 5.5 and not at pH 7.4, is stable to incubation at room temperature for 1 h in the presence or absence of 0.5% Triton X-100 and/or 0.5 m NaCl. The removal of Ca(2+) with chelating agents partially releases the bound PC1. High concentrations of the inhibitory peptide quantitatively release the bound PC1. Taken together, these data support the proposal that proSAAS functions as an endogenous inhibitor of PC1.

Amino Acid Sequence↗

PubMed2003

Subcellular pathways of beta-endorphin synthesis, processing, and release from immunocytes in inflammatory pain.

The opioid peptide beta-endorphin (END) as well as mRNA for its precursor proopiomelanocortin (POMC) are found not only in the pituitary gland, but also within various types of immune cells infiltrating inflamed sc tissue. During stressful stimuli END is released and interacts with peripheral opioid receptors to inhibit pain. However, the subcellular pathways of POMC processing and END release have not yet been delineated in inflammatory cells. The aim of the present study was to examine the presence of POMC, carboxypeptidase E, the prohormone convertases 1 (PC1), and 2 (PC2), PC2-binding protein 7B2, and the release of END from inflammatory cells in rats. Using immunohistochemistry we detected END and POMC alone or colocalized with PC1, PC2, carboxypeptidase E, and 7B2 in macrophages/monocytes, granulocytes, and lymphocytes of the blood and within inflamed sc paw tissue. Immunoelectron microscopy revealed that END is localized within secretory granules packed in membranous structures in macrophages, monocytes, granulocytes, and lymphocytes. Finally, END is released by noradrenaline from immune cells in vitro. Taken together, our results indicate that immune cells express the entire machinery required for POMC processing into functionally active peptides such as END and are able to release these peptides from secretory granules.

Animals↗

PubMed1999

Induction of integral membrane PAM expression in AtT-20 cells alters the storage and trafficking of POMC and PC1.

Peptidylglycine alpha-amidating monooxygenase (PAM) is an essential enzyme that catalyzes the COOH-terminal amidation of many neuroendocrine peptides. The bifunctional PAM protein contains an NH2-terminal monooxygenase (PHM) domain followed by a lyase (PAL) domain and a transmembrane domain. The cytosolic tail of PAM interacts with proteins that can affect cytoskeletal organization. A reverse tetracycline-regulated inducible expression system was used to construct an AtT-20 corticotrope cell line capable of inducible PAM-1 expression. Upon induction, cells displayed a time- and dose-dependent increase in enzyme activity, PAM mRNA, and protein. Induction of increased PAM-1 expression produced graded changes in PAM-1 metabolism. Increased expression of PAM-1 also caused decreased immunofluorescent staining for ACTH, a product of proopiomelanocortin (POMC), and prohormone convertase 1 (PC1) in granules at the tips of processes. Expression of PAM-1 resulted in decreased ACTH and PHM secretion in response to secretagogue stimulation, and decreased cleavage of PC1, POMC, and PAM. Increased expression of a soluble form of PAM did not alter POMC and PC1 localization and metabolism. Using the inducible cell line model, we show that expression of integral membrane PAM alters the organization of the actin cytoskeleton. Altered cytoskeletal organization may then influence the trafficking and cleavage of lumenal proteins and eliminate the ability of AtT-20 cells to secrete ACTH in response to a secretagogue.

Actins↗

PubMed1996

Molecular cloning of prohormone convertase 1 from the atrial gland of Aplysia.

We have screened an Aplysia atrial gland cDNA library using a prohormone convertase (PC)1 probe prepared by polymerase chain reaction (PCR) and have isolated an Aplysia PC1-related full-length 3.6-kb cDNA clone. The cDNA sequence (3,565 bp) encoded a putative preproendoprotease (APC1) of 703 amino acid residues that showed considerable sequence identity with other eukaryotic PC1s, and indicated a high degree of sequence identity with an Aplysia nervous system PC sequence (aPC1B). Northern blot analysis of atrial gland RNA identified two APC1 transcripts of 3.9 kb and 5.0 kb. APC1 is a candidate PC that may play an important role in the processing of egg-laying hormone (ELH)-related precursors in atrial gland secretory cells and represents one of the first examples of PC1 expression in an exocrine tissue.

Animals↗

PubMed1997

Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene.

Human obesity has an inherited component, but in contrast to rodent obesity, precise genetic defects have yet to be defined. A mutation of carboxypeptidase E (CPE), an enzyme active in the processing and sorting of prohormones, causes obesity in the fat/fat mouse. We have previously described a women with extreme childhood obesity (Fig. 1), abnormal glucose homeostasis, hypogonadotrophic hypogonadism, hypocortisolism and elevated plasma proinsulin and pro-opiomelanocortin (POMC) concentrations but a very low insulin level, suggestive of a defective prohormone processing by the endopeptidase, prohormone convertase 1 (PC1; ref. 4). We now report this proband to be a compound heterozygote for mutations in PC1. Gly-->Arg483 prevents processing of proPC1 and leads to its retention in the endoplasmic reticulum (ER). A-->C+4 of the intro-5 donor splice site causes skipping of exon 5 leading to loss of 26 residues, a frameshift and creation of a premature stop codon within the catalytic domain. PC1 acts proximally to CPE in the pathway of post-translational processing of prohormones and neuropeptides. In view of the similarity between the proband and the fat/fat mouse phenotype, we infer that molecular defects in prohormone conversion may represent a generic mechanism for obesity, common to humans and rodents.

Amino Acid Sequence↗

PubMed2004

Perinatal food deprivation induces marked alterations of the hypothalamo-pituitary-adrenal axis in 8-month-old male rats both under basal conditions and after a dehydration period.

Dehydration is a classic homeostatic stressor in rats that leads to a series of endocrine responses including stimulation of the hypothalamo-pituitary-adrenal (HPA) axis. During the last decade, it has been well established that perinatal food restriction is associated with the onset of diseases in adults. Our previous demonstration of long-term alterations in HPA axis activity in both basal conditions and after a 72-hour dehydration period in 4-month-old rats exposed to a 50% maternal food restriction (FR50) in late gestation and lactation prompted us to investigate whether such perinatal undernutrition further affects HPA axis activity in mature animals. As previously described in 4-month-old rats under basal conditions, 8-month-old FR50 rats showed reduced body weight and an enhanced ratio between mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA levels in the hippocampus, as well as increased pro-opiomelanocortin (POMC) mRNA levels in the adenohypophysis. In addition, numerous additional alterations appeared in mature rats. In the hypothalamus, levels of vasopressin (VP) mRNAs were increased both in the paraventricular nucleus (PVN) and in the supraoptic nucleus (SON). In the adenohypophysis, GR and prohormone-convertase 2 (PC2) mRNA levels were significantly increased, whereas prohormone-convertase 1 (PC1) mRNA was not affected by maternal undernutrition. Interestingly, undernourished animals exhibited high plasma levels of total and free corticosterone in spite of normal corticotropin (ACTH) levels, an indication that HPA basal activity is enhanced by maternal undernutrition in 8-month-old animals. Dehydration for 72 h induced a rise in ACTH plasma levels, but did not modify total and free corticosterone plasma levels in 8-month-old FR50 animals. In the adenopituitary, POMC mRNA levels were decreased after dehydration but PC1 mRNA levels were unaffected. The present study indicates that maternal food restriction during the perinatal period dramatically affects the activity of the HPA axis until the age of 8 months. We speculate that higher basal HPA activity and an inadequate HPA response after dehydration in mature animals may contribute to diseases such as hypertension, known to develop with aging in perinatally growth-restricted rats.

Adrenocorticotropic Hormone↗

PubMed1998

Prohormone convertase 1 (PC1) when expressed with pro cholecystokinin (pro CCK) in L cells performs three endoproteolytic cleavages which are observed in rat brain and in CCK-expressing endocrine cells in culture, including the production of glycine and arginine extended CCK8.

Pro CCK was expressed in an L cell line engineered to express PC1 and the products secreted into the media were characterized by a combination of RIA, gel filtration and HPLC. PC1 released from L cells, cleaved pro CCK generating the amino terminal pro peptide. PC1 also generated a peptide which after carboxypeptidase B treatment, was detected with an antiserum specific for CCK Gly. Neither of these peptides was found in media from L cells expressing pro CCK alone. This CCK Gly immunoreactive peptide was similar in size to CCK 8, and after treatment with arylsulfatase and carboxypeptidase B, it co-eluted on HPLC with unsulfated CCK 8 Gly. These results agree with previous studies which support a role for PC1 in generation of CCK 8. This is the first demonstration that PC1 acting alone is able to cleave pro CCK liberating the amino terminal pro peptide and a glycine and arginine extended CCK 8 which is the immediate precursor of CCK 8 amide.

Amino Acid Sequence↗