14 results on '"Pell, J."'
Search Results
2. Regulation of IGF-I mRNA by GH: putative functions for class 1 and 2 message.
- Author
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O'Sullivan DC, Szestak TA, and Pell JM
- Subjects
- Animals, Animals, Newborn, Blood metabolism, Drug Administration Schedule, Growth Hormone administration & dosage, Growth Hormone pharmacology, Liver drug effects, Liver metabolism, Osmolar Concentration, Polyribosomes metabolism, Promoter Regions, Genetic physiology, Protein Biosynthesis, RNA Splicing, RNA, Messenger classification, Reference Values, Sheep, Growth Hormone physiology, Insulin-Like Growth Factor I genetics, RNA, Messenger metabolism
- Abstract
This study investigated mechanisms regulating hepatic insulin-like growth factor (IGF)-I class 1 and 2 mRNA levels. Lambs were treated with growth hormone (GH) either as an acute, single dose or over a longer term. Total hepatic unspliced, pre-mRNA levels increased after the single dose of GH but were attenuated after 8 days of GH, with exon 1- and 2-derived pre-mRNA levels displaying coordinate responses. Surprisingly, changes in total spliced, mature mRNA levels did not reflect those for pre-mRNA, instead being augmented after 8 days of GH. GH also induced a differential increase in the ratio of mature class 2-to-class 1 IGF-I mRNA; therefore, this must be predominantly via posttranscriptional mechanisms. Increases in the ratio of class 2-to-class 1 mRNA were observed in polysomal vs. total RNA preparations derived from GH-treated but not control lambs, indicating an increased proportion of class 2 transcripts engaged in translation. Our findings indicate that GH may stabilize mature class 2 transcripts or destabilize mature class 1 transcripts and that class 2 mRNA may have a greater translational potential. The following two main functions of hepatic class 2 IGF-I mRNA are suggested: an efficient "monitor" of GH status via providing a rapid negative feedback mechanism and a coordinator of endocrine-regulated tissue growth.
- Published
- 2002
- Full Text
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3. Regulation of hepatic insulin-like growth factor I leader exonusage in lambs: effect of immunization against growth hormone-releasing factor and subsequent growth hormone treatment.
- Author
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O'Sullivan DC, Szestak TA, and Pell JM
- Subjects
- Age Factors, Alternative Splicing, Animals, Antibodies blood, Body Composition, Exons, Gene Expression, Growth Hormone metabolism, Immunization veterinary, Insulin-Like Growth Factor Binding Proteins blood, Insulin-Like Growth Factor I genetics, RNA, Messenger metabolism, Sheep immunology, Weight Gain immunology, Growth Hormone physiology, Growth Hormone-Releasing Hormone immunology, Insulin-Like Growth Factor I metabolism, Liver physiology, Sheep growth & development
- Abstract
The establishment of a GH-responsive endocrine IGF-I network is essential for the regulation of postnatal growth. Transcripts of exons 1 and 2 of the mammalian IGF-I gene are alternately spliced onto exon 3, generating class 1 and class 2 mRNA, respectively, each encoding individual signal peptides. The liver is largely responsible for the synthesis of circulating IGF-I and is the main site of expression for class 2 mRNA. The aim of this study was to examine the regulation of hepatic class 1 and 2 mRNA levels in response to changed GH status. Lambs were actively immunized against GRF to suppress GH secretion; hepatic IGF-I mRNA leader exon usage was examined in the presence and absence of GH replacement and in control-immunized lambs. Lambs immunized against GRF exhibited a 17% (P < 0.001) decrease in growth rate as assessed by whole body weight gain, accompanied by decreased circulating IGF-I concentrations (P < 0.001), which were increased by subsequent GH treatment (P < 0.001). Hepatic class 1 and 2 IGF-I mRNA levels decreased in GRF-immunized lambs, although only class 2 transcripts decreased significantly (P < 0.001). Subsequent GH treatment induced increases in class 1 and 2 mRNA levels (P < 0.001) but the increase in class 2 message exceeded that for class 1 (P < 0.001). Thus, the percentage of total IGF-I mRNA accounted for by class 2 mRNA was 45% in control lambs, decreased to less than 20% in GRF-immunized lambs, but increased to 72% in the GRF-immunized lambs treated with GH and correlated with circulating IGF-I concentrations. These data suggest physiological significance for class 1 and 2 IGF-I mRNA species in GH action. Possible functions for such alternative splicing mechanisms are discussed.
- Published
- 2002
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4. Enhancement of insulin-like growth factor I activity by novel antisera: potential structure/function interactions.
- Author
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Pell JM, Hill RA, Stewart CE, Weston CR, and Flick-Smith HC
- Subjects
- Amino Acid Sequence, Animals, Cattle, Cell Line, Cysteine, Dwarfism physiopathology, Epitopes analysis, Fibroblasts, Humans, Insulin chemistry, Insulin-Like Growth Factor I physiology, Insulin-Like Growth Factor II chemistry, Mice, Mice, Mutant Strains, Models, Molecular, Molecular Sequence Data, Nuclear Magnetic Resonance, Biomolecular, Protein Structure, Secondary, Recombinant Proteins chemistry, Recombinant Proteins immunology, Recombinant Proteins pharmacology, Sequence Alignment, Sequence Homology, Amino Acid, Serine, Vertebrates, Weight Gain drug effects, Immune Sera pharmacology, Insulin-Like Growth Factor I chemistry, Insulin-Like Growth Factor I pharmacology
- Abstract
Insulin-like growth factor I (IGF-I) is essential for normal growth and development, regulating cell proliferation, differentiation, and survival. Little IGF-I exists in the free form; rather, it is bound to one of a family of six specific IGF-binding proteins (IGFBPs). Usually, IGFBPs have a high affinity for IGF-I and inhibit its activity. Intriguingly, some IGFBPs also potentiate IGF-I action; the precise mechanism of this is unclear, but it is thought to include modification of the IGFBP to lower its affinity for IGF-I. We have previously generated a novel antihuman (h) IGF-I antiserum that, instead of inhibiting IGF-I activity, enhances it in vivo. As the enhancing anti-IGF-I antiserum and potentiating IGFBPs share several properties with regard to IGF action, the antibody may provide a model for examining the actions of enhancing IGFBPs. In this study we demonstrate that the antiserum can also enhance IGF-I activity in vitro, assessed as cell number of a bovine fibroblast cell line, suggesting that its actions might not merely be confined to changing the kinetics of IGF-I clearance or degradation. Epitope scanning using overlapping octamer and hexamer peptides spanning the entire sequence of IGF-I indicates that the enhancing antiserum recognizes a specific linear region spanning the C-terminal region of the C domain and the proximal A domain (residues Ser33 to Cys47), and that this recognition is not present in nonenhancing antisera. Further, this region is located on the opposite surface of IGF-I from putative type 1 receptor-binding residues, allowing the possibility that the antiserum might be able to modulate IGF-I receptor binding. Antibodies raised against a synthetic peptide corresponding to Ser33 to Cys47 of IGF-I also potentiated IGF-I activity in vivo. As IGF-I may be beneficial in various clinical conditions associated with catabolism or cell repair, we suggest that this potentiating anti-IGF-I antiserum has favorable properties that could form a basis for therapeutic strategy.
- Published
- 2000
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- View/download PDF
5. Regulation of insulin-like growth factor I (IGF-I) bioactivity in vivo: further characterization of an IGF-I-enhancing antibody.
- Author
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Hill RA and Pell JM
- Subjects
- Animals, Binding Sites, Epitopes, Female, Growth Hormone pharmacology, Humans, Hypoglycemia prevention & control, Immune Sera metabolism, Insulin-Like Growth Factor Binding Proteins metabolism, Insulin-Like Growth Factor I metabolism, Male, Mice, Rats, Sheep, Antibodies pharmacology, Insulin-Like Growth Factor I pharmacology
- Abstract
We have previously demonstrated the ability of a polyclonal antibody raised against human insulin-like growth factor I (IGF-I) to potentiate, rather than inhibit, the growth-promoting activity of IGF-I. The anti-IGF-I Ig had a modest affinity for IGF-I, protected IGF-I from degradation, and reduced the IGF-I clearance rate while allowing efficient transfer of peptide from the circulation, leading to the suggestion that the antiserum might be behaving in an analogous manner to enhancing IGF-binding proteins (IGFBPs). The purpose of these studies was to investigate further the characteristics of this antiserum as a means of assessing the importance of IGF-I associated with circulating high mol wt IGFBPs to serve as a bioavailable reservoir of IGF-I peptide. 1) Epitope scanning using sequential and overlapping peptides spanning the entire length of IGF-I revealed one major linear region of anti-IGF-I Ig binding to IGF-I comprising the C-terminal region of the C-domain and the N-terminal region of the A-domain (Arg36-Ile43), a region not associated with receptor or IGFBP binding. 2) The fact that the antibody could potentiate IGF-I whether administered as a preincubated complex or separately indicated that complex formation could occur in the presence of IGFBPs in vivo. 3) The ability of the antibody to attenuate the acute hypoglycemic actions of IGF-I and LR3IGF-I was assessed by pretreating dwarf rats with either anti-IGF-I Ig or nonimmune Ig; 1 h after s.c. administration of peptide, plasma glucose levels decreased by about 4 mM (P < 0.001) in rats pretreated with nonimmune Ig. The duration of hypoglycemia was more prolonged in the LR3IGF-I-treated rats (P < 0.01). Neither IGF-I or LR3IGF-I induced any decrease in circulating glucose concentrations in the rats pretreated with the anti-IGF-I Ig, suggesting that the antibody gave protection against inappropriate acute IGF-induced hypoglycemia. 4) The potentiating effects of the anti-IGF-I Ig on the anabolic actions of IGF-I and LR3IGF-I were compared in dwarf mice. The anti-IGF-I Ig potentiated the increase in whole body weight gain induced by IGF-I by over 3-fold (P < 0.001), but did not change the anabolic action of LR3IGF-I despite its ability to double circulating levels of both IGF peptides. It is, therefore, possible that part of the mechanism of action of the anti-IGF-I Ig involves transfer of IGF-I to smaller mol wt binding proteins. These data confirm the potential of IGFBP-associated IGF-I to act as a reservoir of peptide and to regulate IGF-I activity in vivo.
- Published
- 1998
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6. Actions of an IGF-I-enhancing antibody on IGF-I pharmacokinetics and tissue distribution: increased IGF-I bioavailability.
- Author
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Hill RA, Flick-Smith HC, Dye S, and Pell JM
- Subjects
- Animals, Biological Availability, Chromatography, Female, Immunoglobulins pharmacology, Iodine Radioisotopes pharmacokinetics, Metabolic Clearance Rate, Rats, Rats, Mutant Strains, Tissue Distribution, Immune Sera pharmacology, Insulin-Like Growth Factor I immunology, Insulin-Like Growth Factor I pharmacokinetics
- Abstract
We have previously demonstrated that a specific anti-IGF-I antibody will enhance the growth-promoting activity of IGF-I in vivo (Stewart et al. 1993). Since the antibody had a modest affinity for IGF-I we suggested that the antiserum might protect IGF-I from degradation whilst maintaining it in a bioavailable form. The aim of this investigation was to test that hypothesis by determining the plasma clearance and tissue distribution of tracer IGF-I in the presence of the enhancing anti-IGF-I immunoglobulin (anti-IGF-I Ig) or non-immune immunoglobulin (NI Ig). Dwarf rats were treated with saline, NI Ig or anti-IGF-I Ig for 4 days. On day 4, 125I-IGF-I (1.6 x 10(7) c.p.m.) was injected into the jugular vein and blood sampled over the next 330 min when the rats were killed: samples of liver, kidney and skeletal muscle were quickly dissected out. Mean plasma trichloroacetic acid (TCA)-precipitable 125I-IGF-I was always significantly greater (P < 0.001 for each time point) from anti-IGF-I Ig rats versus the NI Ig or saline groups (which exhibited practically identical decay curves), implying increased binding capacity for IGF-I in the anti-IGF-I Ig rats. Pharmacokinetic parameters were calculated by resolution of the decay curves using a two-phase model. The total clearance rate of 125I-IGF-I was significantly decreased (P < 0.001) by almost twofold in the anti-IGF-I versus the two control groups, consistent with the increased binding capacity in the anti-IGF Ig rats. The half-lives of the faster-decaying phase were not significantly different between treatment groups but, surprisingly, that for the slower-decaying phase was significantly decreased (P < 0.001) in the anti-IGF-I Ig rats versus the two control groups; this may reflect the low affinity of the anti-IGF-I Ig for IGF-I and its enhancing properties. The degradation of 125I-IGF-I was significantly decreased in animals receiving the anti-IGF-I Ig. In support of this, kidney TCA-precipitable radioactivity (c.p.m.) was seven-fold less (P < 0.001) in the anti-IGF-I Ig groups versus the controls, indicative of reduced excretion. Liver TCA-precipitable radioactivity was increased (P < 0.001) in the anti-IGF-I Ig rats, probably due to reticuloendothelial clearance of non-self antibodies: skeletal muscle TCA-precipitable radioactivity tended to increase in the anti-IGF-I Ig group versus the controls which might indicate increased targeting of IGF-I to muscle. Size exclusion chromatography of plasma 15 and 120 min after administration of 125I-IGF-I demonstrated a broad peak of radioactivity with a molecular mass of 150-300 kDa in the anti-IGF-I Ig-treated rats, which was responsible for more than 90% of the eluted radioactivity. This suggests that: (1) 125I-IGF-I was bound to the anti-IGF-I Ig and might also be able to associate with IGFBPs or (2) the polyclonal antibody might recognise more than one antigenic site on IGF-I. These data indicate that the anti-IGF-I Ig was protecting IGF-I from degradation, leading to a large plasma pool of IGF-I but that IGF-I could be transferred readily from the plasma pool to tissues. We suggest that administration of IGF-I in conjunction with a binding molecule similar to the antibody described here could provide the basis for effective IGF-I treatment strategy.
- Published
- 1997
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7. Effects of growth hormone administration and dietary protein intake on insulin-like growth factor I and growth hormone receptor mRNA Expression in porcine liver, skeletal muscle, and adipose tissue.
- Author
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Brameld JM, Atkinson JL, Saunders JC, Pell JM, Buttery PJ, and Gilmour RS
- Subjects
- Adipose Tissue chemistry, Animals, Blood Glucose analysis, Carrier Proteins genetics, Carrier Proteins metabolism, Carrier Proteins physiology, Exons, Gene Expression Regulation, Insulin blood, Insulin-Like Growth Factor I analysis, Insulin-Like Growth Factor I metabolism, Liver chemistry, Male, Muscle, Skeletal chemistry, RNA, Messenger analysis, RNA, Messenger genetics, Random Allocation, Receptors, Somatotropin analysis, Receptors, Somatotropin metabolism, Swine metabolism, Transcription, Genetic, Adipose Tissue metabolism, Dietary Proteins pharmacology, Growth Hormone pharmacology, Insulin-Like Growth Factor I genetics, Liver metabolism, Muscle, Skeletal metabolism, RNA, Messenger metabolism, Receptors, Somatotropin genetics, Swine genetics
- Abstract
The effects of growth hormone (GH) and dietary protein on expression of IGF-I and GH receptor (GHR) genes in liver, muscle, and fat of pigs were investigated. Forty-eight intact male Large White x Landrace pigs were allotted to eight treatment groups (four diets with or without GH). The pigs were restriction-fed one of four diets, which differed only in their protein content (9.9, 13.1, 16.2, and 19.4%, as-fed basis), for a total of 3 wk. The pigs were then injected intramuscularly with either porcine GH (50 micrograms.kg-1.d-1 of rpST) or vehicle for the last 7 d. Pigs were slaughtered 4 h after the final injection. Total RNA was extracted from all tissues and then RNase protection assays were performed to measure expression of IGF-I and GHR genes. Expression of IGF-I mRNA was found to be GH responsive in the liver, semitendinosus (ST), and adipose tissue (P < .01) but not in longissimus muscle (LD). Dietary protein increased IGF-I expression only in the adipose tissue (P < .01). Expression of class 2 transcripts of IGF-I were observed only in the livers of GH-treated pigs, with no effect of dietary protein. Expression of GHR mRNA was found to increase with GH administration in liver and skeletal muscle (LD and ST, P < .05) but not in adipose tissue. There were diet x GH interactions on GHR expression in liver, ST, and adipose tissue, resulting in the highest GHR expression being in the high protein-fed, GH-treated group for liver, but in the low protein-fed, GH-treated group for muscle and adipose tissue. This study demonstrates tissue-specific control of expression of the two genes and also tissue-specific promoter usage (IGF-I exon 2 in liver) in response to GH administration.
- Published
- 1996
- Full Text
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8. Further characterisation of an IGF-I enhancing antibody: actions on IGF-I-induced hypoglycaemia and interaction with the analogue LR3IGF-I.
- Author
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Pell JM, Flick-Smith HC, Dye S, and Hill RA
- Subjects
- Animals, Antibody Formation, Body Weight, Enzyme-Linked Immunosorbent Assay, Humans, Insulin-Like Growth Factor I metabolism, Insulin-Like Growth Factor I pharmacology, Metabolic Clearance Rate, Rats, Tissue Distribution, Antibodies, Blocking physiology, Hypoglycemia chemically induced, Insulin-Like Growth Factor I analogs & derivatives, Insulin-Like Growth Factor I immunology
- Abstract
We have previously shown that a polyclonal anti-IGF-I antiserum administered together with IGF-I potentiates IGF-I activity in vivo. The anti-IGF-I antiserum has a modest affinity for IGF-I, similar to that for enhancing IGFBPs, and treated animals have significantly higher circulating IGF-I concentrations than their controls. Our recent findings have demonstrated that the anti-IGF-I activity decreases the clearance of IGF-I by at least 2-fold and that it abolishes the acute hypoglycaemic action of a single subcutaneous dose of IGF-I. Interestingly, we have been unable to demonstrate potentiation of the growth-promoting activity of the potent non-IGFBP binding IGF-I analogue LR3IGF-I, even though the analogue binds to the antiserum in vitro; rather native IGF-I/antibody complexes perform even better than LR3IGF-I. In IGF-I/antibody-treated dwarf rats, most IGF-I may be found in an uncharacterised high molecular weight antibody complex which is probably responsible for improved IGF-I performance. Thus, the anti-IGF-I antibody may be behaving in a similar manner to a high molecular weight IGFBP and is effective in potentiating IGF-I action in vivo.
- Published
- 1995
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9. Interactions between growth hormone and nutrition in hypophysectomized rats: body composition and production of insulin-like growth factor-I.
- Author
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Bates PC, Loughna PT, Pell JM, Schulster D, and Millward DJ
- Subjects
- Animals, Body Composition drug effects, Heart growth & development, Insulin blood, Insulin-Like Growth Factor I genetics, Liver growth & development, Liver metabolism, Male, Muscle Development, Muscles metabolism, RNA, Messenger analysis, Rats, Rats, Sprague-Dawley, Animal Nutritional Physiological Phenomena, Body Composition physiology, Growth Hormone pharmacology, Hypophysectomy, Insulin-Like Growth Factor I metabolism
- Abstract
Hypophysectomy of adult rats results in a loss of body growth which can be reversed by treatment with GH. The increased growth caused by administration of GH is accompanied by an increase in food consumption. The effects of GH and interactions with nutrition were investigated by treating hypophysectomized rats with GH and either providing unrestricted food or preventing the increased food consumption by pair-feeding with the same intake as that of the hypophysectomized animals. Over the 7-day experimental period, the GH-treated animals grew significantly when food was available ad libitum but did not gain body weight when an increase in food intake was prevented. However, there was a significant interaction between GH and nutrition on body composition; GH significantly decreased body fat and increased the protein: fat ratio only in the animals with the restricted intake. Gastrocnemius muscle weight was increased by GH regardless of food intake, but heart weight did not increase and liver weight was actually decreased by GH treatment when food intake was restricted. Serum concentrations of insulin and insulin-like growth factor-I (IGF-I) were increased by GH in the rats with food available ad libitum but not in the pair-fed rats. However, the liver concentration of IGF-I and its mRNA were increased by GH although the increase in IGF-I mRNA was modulated by the restricted food intake. The decreased weight of the liver in the pair-fed GH-treated rats, despite the increase in IGF-I mRNA, suggests that IGF-I does not influence liver growth. In the gastrocnemius muscle, however, GH increased IGF-I mRNA concentration similarly in both rats with food available ad libitum and in pair-fed rats. Decreased nutrition therefore modulated the action of GH but emphasized its nutrient partitioning effect, thus increasing the anabolic drive towards skeletal muscle growth; this appeared to be mediated by the local production of IGF-I within the muscle.
- Published
- 1993
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10. Potentiation of insulin-like growth factor-I (IGF-I) activity by an antibody: supportive evidence for enhancement of IGF-I bioavailability in vivo by IGF binding proteins.
- Author
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Stewart CE, Bates PC, Calder TA, Woodall SM, and Pell JM
- Subjects
- Animals, Antibodies metabolism, Female, Immune Sera immunology, Insulin-Like Growth Factor Binding Proteins, Insulin-Like Growth Factor I immunology, Insulin-Like Growth Factor I pharmacology, Male, Mice, Mice, Mutant Strains, Rats, Rats, Mutant Strains, Recombinant Proteins immunology, Sheep immunology, Weight Gain, Carrier Proteins physiology, Dwarfism physiopathology, Immunization, Passive, Insulin-Like Growth Factor I physiology
- Abstract
The effects of ovine polyclonal antibodies raised against human recombinant IGF-I were investigated in GH-deficient rodents in vivo both in the presence and absence of exogenous IGF-I. Dwarf mice (negligible endogenous serum IGF-I) treated with anti-IGF-I serum which had been pre-incubated with IGF-I exhibited a significantly greater rate of daily weight gain than did mice treated with the same dose of IGF-I alone (P < 0.001) or even a 2.5-fold higher dose (P < 0.001). Similar increases in whole body weight gain were observed in dwarf rats, with a concomitant increase in dissected muscle weight. Serum IGF-I concentrations were greater in all animals treated with the complex of anti-IGF-I antibodies and IGF-I than in those administered only IGF-I. Size exclusion chromatography of dwarf rat serum indicated the presence of high mol wt material (> 160 kDa) capable of binding 125I-IGF-I in the anti-IGF-I treated rats. We suggest that this particular polyclonal antibody is behaving in a similar manner to an enhancing IGF binding protein, maintaining a reservoir of bioactive IGF-I. Since the antibody has a slightly lower affinity (2 x 10(8) liters/M) than that of the type 1 receptor, these data provide tentative indirect evidence to support the hypothesis that the recently discovered mechanisms which apparently decrease the affinities of several IGFBPs may indeed result in increased IGF-I bioavailability.
- Published
- 1993
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11. Differential regulation of transcription initiation from insulin-like growth factor-I (IGF-I) leader exons and of tissue IGF-I expression in response to changed growth hormone and nutritional status in sheep.
- Author
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Pell JM, Saunders JC, and Gilmour RS
- Subjects
- Animals, Base Sequence, Gene Expression, Liver physiology, Molecular Probes genetics, Molecular Sequence Data, Muscles physiology, RNA, Messenger genetics, Animal Nutritional Physiological Phenomena, Exons physiology, Growth Hormone metabolism, Insulin-Like Growth Factor I genetics, Insulin-Like Growth Factor I metabolism, Transcription, Genetic physiology
- Abstract
In the mammalian insulin-like growth factor-I (IGF-I) gene, exons 1 and 2 are differentially spliced to exon 3 producing alternate class 1 and class 2 transcripts. The aim of this study was to investigate the tissue expression of these leader exons in lambs growing at different rates as a result of chronic manipulation of nutritional and GH status. Riboprobes were developed so that leader exon-specific and total IGF-I gene expression could be determined using a single RNase protection assay. Lambs were fed a diet containing high or low protein content either ad libitum or at a restricted intake; within these dietary groups they were treated with either saline or GH for 10 weeks. Total hepatic IGF-I messenger RNA (mRNA) transcripts were significantly increased by GH (P = 0.004), protein (P = 0.002), and energy (P < 0.001) status as were circulating IGF-I concentrations (GH, P < 0.001; protein, P = 0.026; energy, P < 0.001). Exons 1 and 2 were expressed in liver but to a variable extent. Increased dietary energy and protein induced increased expression from both class 1 and 2 transcripts, but the percent increases was at least 5-fold greater for class 2 than for class 1 mRNA. GH treatment only stimulated significant increases in expression from class 2 transcripts. In the low protein, energy-restricted, saline-treated lambs exon 1 transcripts accounted for approximately 70% of total class 1 and 2 transcripts, and this proportion declined significantly as class 1 and 2 transcripts, and this proportion declined significantly as GH and nutritional status increased to only 30% in the high protein, ad libitum-fed, GH-treated animals; class 2 transcripts therefore displayed the opposite pattern of expression. These data indicate that exon 2 may be far more sensitive than exon 1 in intact animals which have been stimulated within normal physiological limits. Muscle IGF-I gene expression was at least 20-fold less than that for the liver and consisted mainly of class 1 transcripts. Muscle total IGF-I mRNA was insensitive to changed nutritional status or to GH treatment, even though significant increases in muscle growth occurred in response to ad libitum intake and GH, indicating that hepatically derived endocrine IGF-I could have a role in the regulation of muscle growth.
- Published
- 1993
- Full Text
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12. Differential regulation of IGF-I leader exon transcription.
- Author
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Pell JM and Gilmour RS
- Subjects
- Animals, Body Weight, Exons, Gene Expression Regulation drug effects, Growth Hormone blood, Insulin-Like Growth Factor I metabolism, Liver drug effects, Nutritional Status, Organ Size, RNA, Messenger metabolism, Receptor, IGF Type 1 biosynthesis, Receptors, Somatotropin biosynthesis, Restriction Mapping, Sheep, Transcription, Genetic, Gene Expression Regulation physiology, Growth Hormone pharmacology, Insulin-Like Growth Factor I biosynthesis, Insulin-Like Growth Factor I genetics, Liver metabolism, Muscles metabolism, Protein Sorting Signals biosynthesis
- Abstract
We have shown that there is differential expression of the two IGF-I leader exons during physiological changes in GH and nutritional status in liver, with exon 2 being more responsive than exon 1. It may be that this exon is responsible for endocrine IGF-I synthesised in response to specific anabolic stimuli inducing subsequent whole body and skeletal muscle growth.
- Published
- 1993
- Full Text
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13. Differential actions of growth hormone and insulin-like growth factor-I on tissue protein metabolism in dwarf mice.
- Author
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Pell JM and Bates PC
- Subjects
- Animals, Blood Glucose analysis, Insulin-Like Growth Factor I metabolism, Liver metabolism, Mice, Muscles metabolism, Myocardium metabolism, Weight Gain drug effects, Dwarfism metabolism, Growth Hormone pharmacology, Insulin-Like Growth Factor I pharmacology, Proteins metabolism
- Abstract
The actions and interactions of exogenous insulin-like growth factor-I (IGF-I) and bovine GH (bGH) on protein metabolism were investigated in vivo using Snell dwarf mice. Mice were administered a daily dose of 1.5 or 20 micrograms bGH in the presence or absence of 20 micrograms IGF-I. IGF-I and GH stimulated significant increases in whole body weight gain. Serum IGF-I concentrations increased dramatically in mice administered IGF-I, but more modestly in GH-treated mice. However, greater increases in tissue IGF-I content were observed for GH- than for IGF-treated mice, implying that GH exerted its anabolic actions by local IGF-I synthesis. Skeletal muscle (combined gastrocnemius plus plantaris) weight was significantly increased in GH-treated mice and tended to increase in IGF-treated mice. Muscle protein synthesis was stimulated by about 50% in mice treated with IGF-I alone and the lower dose of GH and by over 100% in the group treated with 20 micrograms/day GH compared with that in saline-treated mice; further additive increases in synthesis rates were observed for mice administered both IGF-I and GH. In all cases, this stimulation was due to both increased RNA content and efficiency of protein synthesis, expressed as grams of protein synthesized per g RNA/day. Liver weight and protein synthetic rate were increased by as much as 25% and 34%, respectively, in GH-treated mice, but IGF-I inhibited hepatic protein metabolism, tending to decrease synthesis rates and inducing a decrease in the efficiency of protein synthesis. Thus, IGF-I and GH have specific and differential effects on tissue protein metabolism in this model.
- Published
- 1992
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14. Expression of a growth hormone-responsive exon of the ovine insulin-like growth factor-I gene.
- Author
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Saunders JC, Dickson MC, Pell JM, and Gilmour RS
- Subjects
- Amino Acid Sequence, Animals, Base Sequence, DNA, Insulin-Like Growth Factor I metabolism, Molecular Sequence Data, Restriction Mapping, Sheep, Transcription, Genetic, Exons, Gene Expression Regulation, Growth Hormone physiology, Insulin-Like Growth Factor I genetics
- Abstract
The sheep insulin-like growth factor-I (IGF-I) gene encodes mRNAs containing three different 5'-untranslated sequences as a consequence of alternate splicing of leader exons. Using a combination of RNase protection and primer extension assays, we have mapped the transcriptional start sites of one of the leader exons, exon 1A. Transcription from exon 1A appeared to initiate from multiple points within a 20 bp region situated about 60 bp upstream of the exon 1A splice site. The presence of this transcript in the liver of animals treated with GH was enhanced five- to tenfold and contributed to about 95% of the total hepatic increase in IGF-I mRNA. This exon is generally expressed in a number of tissues immediately after birth; by about 4 weeks postpartum, however, expression is confined to liver. The regulation of hepatic and non-hepatic IGF-I synthesis by GH may involve different mechanisms.
- Published
- 1991
- Full Text
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