Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.1.1.32 (phosphoenolpyruvate carboxykinase)
4,204 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transgenic mice, expressing the gene for bovine growth hormone (bGH), exhibit increased body size, reduced reproductive capacity, and high basal levels of several hormones including corticosterone. Their shortened life span may be indicative of accelerated aging. As prominent astrogliosis of the CNS accompanies aging in rodents, bGH transgenic mice were examined for astrogliosis, as quantified by an ELISA for the astrocyte-localized protein, glial fibrillary acidic protein (GFAP). Transgenic mice were produced by mating C57BL/6 x C3H F1 hybrid females with male descendants of animals produced by microinjection of fertilized eggs with phosphoenolpyruvate carboxykinase (PEPCK)/bGH-hybrid gene. Transgenic mice (approximately 3.5 and approximately 12 months of age) weighed significantly more than same age or older (approximately 20 month) controls. Most of their internal organs, including the heart, kidneys, adrenals, liver, and spleen, were also heavier. In contrast, the thymus was heavier only in the younger transgenic mice. Serum corticosterone was highest in the older transgenic mice. A small but significant increase in whole brain, cortex, and cerebellar weight, relative to controls and the older transgenic mice, was found in the younger transgenic mice. Control mice exhibited large, significant age-related increases in GFAP. Increases of 35, 70, 68, 89, 79, and 95% for cortex, cerebellum, striatum, hippocampus, midbrain, and brain stem, respectively, were found when comparing the oldest (approximately 20 months) control mice to the youngest (approximately 3.5 months). In contrast, in the olfactory bulbs and the hypothalamus there were no age-related changes in the levels of GFAP in control mice. Transgenic mice (approximately 3.5 months) had significantly elevated GFAP levels relative to the same-age controls in all brain areas examined. In some brain areas, the GFAP levels found in the younger transgenic mice were equivalent to those found in the oldest controls. No differences between controls and transgenics were found in tyrosine hydroxylase protein levels of striatum or hypothalamus. The elevated GFAP levels of transgenic mice may reflect increased neural damage due to accelerated aging processes or damage associated with high circulating levels of bGH or corticosterone. Alternatively, the increased expression of GFAP in the transgenic mice may reflect altered regulation of GFAP rather than an increase signaled by neural damage.
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PMID:Increased glial fibrillary acidic protein (GFAP) levels in the brains of transgenic mice expressing the bovine growth hormone (bGH) gene. 755 16

As part of an ongoing search for diabetes susceptibility loci, we tested linkage with non-insulin-dependent diabetes mellitus (NIDDM) for 19 candidate loci or regions chosen for their potential to affect directly or indirectly the action of insulin. Loci were associated with insulin resistance, known effects on lipid metabolism, or effects on glucose metabolism or insulin action. Loci included the insulin-responsive (GLUT4) glucose transporter, hexokinase 2, glucagon, growth hormone, insulin receptor substrate 1 (IRS1), phosphoenolpyruvate carboxykinase, hepatic and muscle forms of pyruvate kinase, hepatic phosphofructokinase, the apolipoprotein B and the apolipoprotein A2 cluster, lipoprotein lipase, hepatic triglyceride lipase, the very-low-density-lipoprotein receptor, and the Pima insulin resistance locus on chromosome 4. For several candidates, no specific informative marker was available; consequently, we tested the surrounding region with highly informative markers. These regions included the diabetes-associated ras-like gene, rad, and the cholesterol ester-transfer gene, both mapped to chromosome 16. Additionally, we tested for linkage with markers at the tumor necrosis factor-alpha gene and the Friedreich's ataxia region. All regions were tested for linkage with microsatellite polymorphisms in > 450 individuals from a minimum of 16 Caucasian families under parametric (LINKAGE 5.1) and nonparametric (affected pedigree member) models.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Linkage analysis of 19 candidate regions for insulin resistance in familial NIDDM. 758 21

Transgenic mice overexpressing the phosphoenolpyruvate carboxykinase/bovine growth hormone (PEPCK/bGH) hybrid gene and normal (nontransgenic) littermate controls (10 males + 10 females/group) were given access to tapwater and an ascending series of concentrations of ethanol (1.0-22.0%), then a similar ascending series of concentrations of nicotine (1.0-40.0 micrograms/ml), in a two-bottle choice test. Male transgenic mice consumed more and exhibited greater preferences for ethanol and nicotine than control males; transgenic females consumed less and showed lower preferences for ethanol, but not nicotine, than control females. These results suggest that chronic exposure to high levels of bGH may modulate the rewarding effects of ethanol and nicotine in mice in a gender-specific fashion.
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PMID:Ethanol and nicotine consumption and preference in transgenic mice overexpressing the bovine growth hormone gene. 761 2

Both physiological and excessive levels of growth hormone (GH) can affect reproductive functions. Overexpression of human (h) or bovine (b) GH in transgenic female mice was previously reported to be associated with reproductive deficits. The objectives of the present study were to determine the age of onset of puberty, the length of the estrous cycle, and the ovulation rate in transgenic and normal mice from a line expressing bGH with the phosphoenolpyruvate carboxykinase (PEPCK) promoter and characterized by very high levels of transgene expression. Transgenic females reached puberty, defined as the appearance of the vaginal introitus, earlier than their normal littermates, but at a higher body weight. Compared to normal animals, an increased number of transgenic females failed to mate during the 15-day period of observation, and pregnancy rates were reduced. However, ovulation rates, as estimated by counting CL and implantation sites on Day 7 postcoitum, were increased in transgenic females. Plasma bGH levels in transgenic females ranged from 700 to 2200 ng/ml and were negatively correlated with fertility. To assess the effect of bGH on the ovulation rate in non-transgenic mice, normal females were paired with normal males and injected for up to 3 days with either 0.75 mg bGH/day or 0.30 mg bGH/day (injected as a single dose or as 0.15 mg twice daily). Data from animals that mated after at least 2 days of bGH treatment were analyzed. The ovulation rate was increased in females treated with 0.75 mg bGH/day, as compared to controls, and in females injected with 0.15 mg bGH twice daily as compared to those given 0.3 mg bGH/day and to controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of bovine growth hormone (bGH) transgene expression or bGH treatment on reproductive functions in female mice. 762 14

Transgenic female mice overexpressing the bovine growth hormone (bGH) gene with the phosphoenolpyruvate carboxykinase (PEPCK) promoter exhibit severe reproductive deficits. Although these animals ovulate and conceive normally, pregnancy is arrested due to luteal failure, leading to the loss of embryos during early gestation. The results of replacement therapy suggested that luteal failure was secondary to prolactin (PRL) deficiency. The objective of this study was to examine the neuroendocrine control of PRL secretion during early pregnancy in PEPCKbGH-1 transgenic mice. Normal and transgenic littermates were killed by decapitation on Day 7 postcoitum (p.c.) at 1500, 1800, or 2100 h, i.e., the period including the expected diurnal PRL surge in pregnant mice. In normal females, plasma PRL levels were significantly elevated at 1800 h when compared to the levels measured at 1500 or 2100 h, but no temporal variation in PRL levels was found in transgenic mice. In normal females, the content of dopamine in the median eminence was reduced at 1800 h, i.e., at the time of the PRL surge. In contrast, no temporal changes were detected in the median eminence dopamine content in transgenic mice. Twice-daily injections of domperidone, a dopamine receptor blocker, increased the incidence of pregnancy in transgenic females. After treatment with aromatic amino acid decarboxylase inhibitor NSD-1015 on Day 7 p.c., plasma levels of PRL were similarly elevated in transgenic and normal females. However, the accumulation of 5-hydroxytryptophan (5-HTP) in the medial basal hypothalamus after this treatment was significantly smaller in transgenic than in normal females.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Infertility in transgenic mice overexpressing the bovine growth hormone gene: disruption of the neuroendocrine control of prolactin secretion during pregnancy. 762 19

Vitamin A regulation of specific promoter domains of the phosphoenolpyruvate carboxykinase (PEPCK) gene was tested in a PEPCK/bovine growth hormone (bGH) transgenic mouse model. Vitamin A deficiency causes a significant decrease in hepatic bGH mRNA when expression is driven by either a 533-base-pair (bp) PEPCK promoter fragment (from position -460 to +73) or a 428-bp PEPCK promoter fragment (from position -355 to +73). Treatment of vitamin A deficient transgenic mice with all-trans retinoic acid (RA) increases bGH mRNA levels above those measured with the deficiency. Hepatic retinoic acid receptor (RAR)beta mRNA levels also change with vitamin A deficiency and supplementation, but not RAR alpha mRNA levels. These results indicate that all-trans RA plays a physiologic role in regulating expression of a gluconeogenic gene in liver.
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PMID:Effects of vitamin A deficiency and retinoic acid treatment on expression of a phosphoenolpyruvate carboxykinase-bovine growth hormone gene in transgenic mice. 764 27

The hormonal regulation of transcription of the phosphoenolpyruvate carboxykinase (GTP) (4.1.1.32) (PEPCK) gene during diabetes was studied using transgenic mice containing a chimeric gene consisting of segments of the PEPCK promoter (-2000/+73, -460/+73, -355/+73) linked to bovine growth hormone (bGH) reporter gene. The effect of diabetes and insulin on transgenic mice containing a mutation in cAMP regulatory sequences at -90/-82 and -250/-234 was also studied. In addition, we analyzed the transcriptional response of the PEPCK gene to adrenalectomy, the administration of glucocorticoids, and alterations in dietary protein and carbohydrate. Our results indicate that deletion of the insulin regulatory sequence of the PEPCK promoter did not affect dietary control of PEPCK gene expression. However, glucocorticoids and the glucocorticoid regulatory unit appear to be essential for induction of PEPCK gene transcription by diabetes. By contrast, mutation of cAMP regulatory elements of the PEPCK promoter did not limit induction of PEPCK transcription by diabetes, nor did it affect negative regulation of transcription by insulin. These results provide evidence for the interaction of insulin and glucocorticoid regulatory elements in the control of PEPCK gene transcription and suggest an important role of glucocorticoids as a gluconeogenic activator during diabetes.
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PMID:Glucocorticoids regulate the induction of phosphoenolpyruvate carboxykinase (GTP) gene transcription during diabetes. 768 54

The levels and characteristics of growth hormone (GH)-binding protein (GHBP) and the distribution of GH in peripheral circulation between the free and the bound fractions were studied in three lines of transgenic mice with various degrees of overexpression of bovine (b) GH gene. Two serum fractions bound GH specifically: one with low affinity and high capacity (GHBPI) and one with high affinity and low capacity (GHBPII). The GHBP binding capacity in normal mice (both sexes), transgenic male mice that express the metallothionein-I-hybrid bGH genes, transgenic female mice that express phosphoenolpyruvate carboxykinase (PEPCK)-bGH hybrid genes (PEPCK-bGH-1), and transgenic PEPCK-bGH-5 animals was 1.1 +/- 0.2, 2.0 +/- 0.1, 3.0 +/- 0.1, and 3.9 +/- 0.6 pmol/ml serum, respectively. The amount of GH bound to GHBP in transgenic animals vs. normal siblings was increased 1.8-, 2.5-, and 3.9-fold in these three lines. Consequently, the levels of GH-GHBP complexes in the circulation of PEPCK-bGH-1 transgenic mice were increased approximately 10-fold. Specific GHBP radioimmunoassay confirmed a threefold increase in GHBP in PEPCK-bGH-1 transgenic animals. The levels of GHBP were not significantly correlated to serum GH within or between lines, perhaps due to elevation of serum GH in PEPCK-bGH mice above the level producing maximal response. From these and previous studies, we conclude that life-long exposure to supranormal GH levels leads to major shifts in GH binding in the circulation and in the GH target organs.
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PMID:Growth hormone-binding protein in normal mice and in transgenic mice expressing bovine growth hormone gene. 773 75

Transgenic pigs were created that harboured a phosphoenolpyruvate carboxykinase-bovine growth hormone construct (PEPCK-bGH). Four founder animals and two transgenic offspring from one line were evaluated between 6 1/2 and 12 months of age. There was no evidence of severe hepatic or renal lesions in these pigs, which characterised transgenic PEPCK-bGH mice previously described. While glomerular and tubular lesions in kidney sections were not identified in the transgenic pigs, mesangial cell proliferation was observed in two transgenic offspring from a single line. Additionally, glomerular size was significantly increased in four of four puberal transgenic swine when compared to age- and sex-matched controls (28.30 +/- 4.1 vs. 14.2 +/- 2.7 x 10(5) microns 3; representing 3 transgenic lines, p < 0.05). Surprisingly, no mature adipocytes were observed in subcutaneous sections obtained in transgenic GH pigs. Histological evaluation of these transgenic pigs further illustrates the requirement for precise control of growth-related genes and their protein products.
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PMID:Liver, renal and subcutaneous histopathology in PEPCK-bGH transgenic pigs. 800 Apr 35

Overexpression of human (h) or bovine (b) growth hormone (GH) in transgenic mice is associated with marked (2- to 12-fold) and significant increase in hepatic binding of GH and prolactin (PRL). This is due to an increase in the number of GH and PRL receptors (GHR, PRLR) per mg of microsomal protein without changes in binding affinity. Comparison of results obtained in transgenic animals expressing bGH with a mouse metallothionein (MT) or a rat phosphoenolpyruvate carboxykinase (PEPCK) promoter suggests that effects of bGH on hepatic GHR and PRLR do not require GH overexpression during fetal life and, within the dose range tested, the effects on PRLR are not dose dependent. The increase in hepatic GHR was accompanied by significant increases in plasma GH-binding protein (GHBP) and in mean residence time of injected GH. Thus, life-long elevation of peripheral GH levels alters the availability of both free GH and GHR. Site-directed in vitro mutagenesis was used to produce hGH and bGH analogs mutated within one of the sites involved in binding to GHR and PRLR. Mutating hGH to produce amino acid identity with bGH at Position 11, 18 (within Helix 1), 57, or 60 (within the loop between Helix 1 and 2) did not affect binding to GHR in vitro, or somatotropic activity in transgenic mice in vivo but reduced lactogenic activity in Nb2 cells by 22%-45%. Mutations of bGH designed to produce amino acid identity with hGH at one to four of the corresponding positions in the bGH molecule did not interfere with binding to GHR or somatotropic activity in vivo, and failed to produce significant binding to PRLR but resulted in alterations in the effects on the hypothalamic and anterior pituitary function in transgenic mice. Apparently region(s) outside the domains examined are essential for lactogenic activity of hGH, and different portions of the GH molecule are responsible for its diverse actions in vivo.
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PMID:Growth hormone (GH) binding and effects of GH analogs in transgenic mice. 801 52


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