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Query: UNIPROT:P06889 (Mol)
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Insulin increases the synthesis of mitochondrial proteins in the isolated perfused heart and total cell protein synthesis in neonatal cardiac myocytes. Since carnitine-dependent fatty acid oxidation is modulated by insulin in a variety of tissues, the effects of 1.7 microM insulin on the mitochondrial enzyme(s), carnitine palmitoyltransferase (malonyl-CoA-sensitive CPT-I and the matrix-facing CPT-II), were studied in neonatal rat cardiac myocytes cultured in the absence of serum. Following incubation in serum-free medium, there is a four-fold increase in the I50 of CPT-I for malonyl-CoA (3.8 microM) compared to cells cultured in serum-free medium to which insulin has been added (I50 = 0.8 microM). CPT-I activity in the insulin-supplemented, serum-free cultures is 57% higher (P < 0.002) than CPT-I activity in cells cultured in the absence of insulin; CPT-II activity is also significantly increased (P < 0.01) in the presence of insulin. Since CPT-II is an inner membrane protein, the CPT response to insulin may be coordinately regulated with other mitochondrial activities. Similar to CPT, cytochrome oxidase activity of cardiac myocytes in serum-free medium is increased 33% by insulin. Consistent with this finding, both CPT-II and cytochrome oxidase mRNA expression is elevated over control in the presence of insulin. CPT-II activity increases significantly only at very high insulin concentrations (1.7 microM), suggesting a role for insulin-like growth factor pathway. When myocytes are cultured in the presence of 1.7 microM insulin and then transferred to an insulin-free medium, subsequent addition of insulin does not stimulate uptake of deoxyglucose. These results suggest that the response of CPT to insulin is mediated by insulin-like growth factor activity and not by cellular glucose availability. The response of CPT to insulin does not appear to be mediated by the protein kinase C pathway since CPT-II activity is not reduced by the protein kinase C inhibitor, chelerythrine. Insulin significantly increases protein synthesis in the neonatal cardiac myocyte and in isolated mitochondria by increasing incorporation of labelled amino acid into total myocyte and/or mitochondrial protein. The degradation rate of radiolabelled protein in cardiac myocytes cultured in the presence of insulin is not different from that of insulin-deprived cells. The data suggest that insulin can affect the activity and expression of mitochondrial proteins, e.g., CPT, through the insulin-like growth factor-I pathway in neonatal cardiac myocytes.
J Mol Cell Cardiol 1995 Jan
PMID:Insulin-associated changes in carnitine palmitoyltransferase in cultured neonatal rat cardiac myocytes. 776 Mar 80

Exposure to hyperoxia has been demonstrated to alter the cell number of lung fibroblasts in vivo. The precise mechanism of lung fibroblast proliferation after hyperoxic exposure has not been elucidated, however. We examined the growth characteristics of lung fibroblasts isolated from 21-day-old rats exposed to air or 100% O2 for 8 days. Cell proliferation was assessed by hemocytometry, [3H]thymidine incorporation, and fractional labeling with the thymidine analog bromodeoxyuridine. Under all conditions tested, fibroblasts isolated from O2-exposed rats grew more rapidly than those from air-exposed rats. Conditioned medium from fibroblasts isolated from hyperoxia-exposed rats failed to increase the [3H]thymidine incorporation of control cells to that observed in cells isolated from hyperoxia-exposed animals, suggesting that an autocrine growth factor was not responsible for the excess proliferation. Sensitivity to exogenous growth factors was assessed by measuring the response to increasing concentrations of insulin-like growth factor-1 (IGF-1). Relative to 1% fetal bovine serum (FBS), concentrations of IGF-1 between 3 and 30 ng/ml significantly increased the [3H]thymidine incorporation of fibroblasts derived from hyperoxic animals, whereas control cells were unresponsive to IGF-1 stimulation. The apparent sensitivity to IGF-1 led us to assess the effect of in vivo hyperoxic exposure on the expression of c-Ha-ras, which encodes a membrane-bound, GTP-binding/hydrolyzing protein essential for progression through G1 in the cell cycle. ras mRNA levels in quiescent, control cells were minimal but increased following serum stimulation. The c-Ha-ras expression of lung fibroblasts from hyperoxia-exposed animals, on the other hand, was substantial in quiescent cells and remained high after serum exposure.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1995 Jan
PMID:In vivo hyperoxic exposure increases cultured lung fibroblast proliferation and c-Ha-ras expression. 781 67

The genomes of homeothermic (warm-blooded) vertebrates are mosaic interspersions of homogeneously GC-rich and GC-poor regions (isochores). Evolution of genome compartmentalization and GC-rich isochores is hypothesized to reflect either selective advantages of an elevated GC content or chromosome location and mutational pressure associated with the timing of DNA replication in germ cells. To address the present controversy regarding the origins and maintenance of isochores in homeothermic vertebrates, newly obtained as well as published nucleotide sequences of the insulin and insulin-like growth factor (IGF) genes, members of a well-characterized gene family believed to have evolved by repeated duplication and divergence, were utilized to examine the evolution of base composition in nonconstrained (flanking) and weakly constrained (introns and fourfold degenerate sites) regions. A phylogeny derived from amino acid sequences supports a common evolutionary history for the insulin/IGF family genes. In cold-blooded vertebrates, insulin and the IGFs were similar in base composition. In contrast, insulin and IGF-II demonstrate dramatic increases in GC richness in mammals, but no such trend occurred in IGF-I. Base composition of the coding portions of the insulin and IGF genes across vertebrates correlated (r = 0.90) with that of the introns and flanking regions. The GC content of homologous introns differed dramatically between insulin/IGF-II and IGF-I genes in mammals but was similar to the GC level of noncoding regions in neighboring genes. Our findings suggest that the base composition of introns and flanking regions is determined by chromosomal location and the mutational pressure of the isochore in which the sequences are embedded. An elevated GC content at codon third positions in the insulin and the IGF genes may reflect selective constraints on the usage of synonymous codons.
Mol Biol Evol 1994 Nov
PMID:Evolution of base composition in the insulin and insulin-like growth factor genes. 781 27

The regional distribution of nerve growth factor (NGF) and insulin-like growth factor-1 (IGF-1) receptors in human spinal cords from controls and amyotrophic lateral sclerosis (ALS) patients was studied by quantitative autoradiography. High-affinity nerve growth factor receptors were found to be distributed to a similar extent within the various segments of the human spinal cord and predominantly within the substantia gelatinosa of the dorsal horn, whereas no significant binding could be detected in the motor-neuron areas. A similar pattern of binding was obtained in the ALS spinal cords. Moreover, no reexpression of NGF receptors could be demonstrated in the motor-neuron areas of ALS spinal cords. When comparing 125I-IGF-1 binding in the different spinal levels of normal spinal cord, the same distribution pattern was found in which the binding was highest in the central canal > dorsal horn > ventral horn > white matter. In the ALS cases, although a general upregulation of IGF-1 receptors was observed throughout the spinal cord, significant increases were observed in the cervical and sacral segments compared to controls. The cartography of IGF-1 receptors in the normal spinal cord as well as the change of these receptors in diseased spinal cord may be of importance in future treatment strategies of ALS.
Mol Neurobiol
PMID:Growth factor receptors in amyotrophic lateral sclerosis. 788 98

The problem is to discover which of the promoters of the insulin-like growth factor-II gene stimulate the transcription of mRNA which is translated into protein. Three alternative leader exons are attached to the coding sequences in RNA transcribed from this gene in other systems, and it is mainly the paternal allele which is expressed in mouse development. Transcripts bearing each of the three leader exons were found in the RNA from the chorio-allantoic placenta, visceral yolk sac, and embryo, starting at 9.5 days. A varying proportion of one abundant transcript was disengaged from the polysomes at different days of development. This transcript was prefixed by the longest of the three alternative untranslated 5' leader exons (exon 2), and it was consistently associated with polysomes in the choroid plexus and leptomeninges of the brain. Many exon 2 transcripts were abbreviated by endonucleolytic cleavage and lacked a poly(A) tail. In contrast, the transcripts with the shortest leader (exon 3) were mainly displayed on polysomes at all the stages of development which were examined. During mouse development, the production of IGF-II protein must be partly controlled by the mechanisms which regulate translation.
Mol Reprod Dev 1994 Nov
PMID:Discriminating translation of insulin-like growth factor-II (IGF-II) during mouse embryogenesis. 788 64

The mechanism by which steroids influence cell proliferation is poorly understood although an understanding of this process might facilitate the development of strategies to modulate the tissue-specific activity of steroid hormones. In this article, the evidence that steroid hormones interact with the insulin-like growth factor (IGF) signal transduction pathway is reviewed for three different tissues. In osteoblasts, oestradiol stimulates the production of IGF-I which appears to act as an autocrine growth factor. In uterine tissue, oestradiol increases the synthesis of IGF-I in the stroma which then modulates the proliferation of epithelial cells although there is also evidence that oestradiol can modulate the sensitivity of uterine epithelial cells to IGFs. In breast cancer, oestrogens may increase IGF-II synthesis in epithelial cells, increase the sensitivity of breast cancer cells to IGFs (possibly by modulating type I IGF receptor levels) as well as resulting components of the IGF signal transduction pathway resulting in induction of immediate early genes. There therefore appears to be a variety of ways in which oestradiol interact with the IGF signal transduction pathway and these may be applicable to other malignant and normal tissues and other groups of steroid hormones.
J Steroid Biochem Mol Biol 1994 Oct
PMID:Role of insulin-like growth factors in steroid modulated proliferation. 794 43

In the present study, we examined whether insulin-like growth factor-II (IGF-II) induces hypertrophy of cultured neonatal rat cardiomyocytes. IGF-II (10(-7) M) increased the cell surface area of, and the protein content in, cardiomyocytes after 48 h-exposure. IGF-II dose-dependently (10(-10)-10(-7) M) stimulated protein synthesis as evaluated by [3H]leucine incorporation; the maximum response was 1.7-fold increase over control at 10(-7) M. Since the response of cardiac hypertrophy is characterized by enhanced expression of muscle specific genes, effects of IGF-II on steady-state levels of mRNA for myosin light chain 2 (MLC2), troponin I and alpha-actin isoforms (skeletal and cardiac isoforms) were evaluated by Northern blot analysis. IGF-II (10(-7) M) increased mRNA levels for MLC2, troponin I and skeletal alpha-actin, as early as 60 min with a maximum response after 6 h, whereas cardiac alpha-actin mRNA levels were unaffected. Calcium channel blocker, nicardipine, inhibited IGF-II-stimulated skeletal alpha-actin mRNA levels, however, inhibitor of protein kinase C, H-7, unaffected. These results suggest that IGF-II plays a potential role in cardiac hypertrophy.
J Mol Cell Cardiol 1994 Jul
PMID:Insulin-like growth factor-II induces hypertrophy with increased expression of muscle specific genes in cultured rat cardiomyocytes. 796 47

Insulin-like growth factor II (IGF-II) is a mitogen for many cell types and an important modulator of muscle growth and differentiation. IGF-II gene is prevalently expressed during prenatal development and its gene activity is regulated by genomic imprinting, in that the allele inherited from the father is active and the allele inherited from the mother is inactive in most normal tissues. IGF-II expression is activated in several types of human neoplasms and an alteration of IGF-II imprinting has been described in Beckwith-Wiedemann syndrome and Wilms' tumor. Here we show that monoallelic expression of IGF-II gene is conserved in normal adult muscle tissue whereas two or more copies of active IGF-II alleles, arising by either relaxation of imprinting or duplication of the active allele, are found in 9 out of 11 (82%) rhabdomyosarcomas retaining heterozygosity at 11p15, regardless of the histological subtype. Since IGF-II has been indicated as an autocrine growth factor for rhabdomyosarcoma cells, these findings strongly suggest that acquisition of a double dosage of active IGF-II gene is an important step for the initiation or progression of rhabdomyosarcoma tumorigenesis. Among different types of muscle tumors, relaxation of imprinting seems to arise prevalently in rhabdomyosarcomas, since we have detected only one case of partial reactivation of the maternal IGF-II allele out of 7 leiomyosarcomas tested.
Hum Mol Genet 1994 Jul
PMID:Mono- and bi-allelic expression of insulin-like growth factor II gene in human muscle tumors. 798 80

The specific binding sites for growth hormone was recognized on both thymic lymphocytes (thymocytes) and thymus epithelial cells. The somatotropic action of GH is considered to be mediated mainly by insulin-like growth factor-1 (IGF-1) and partially by GH itself. In this study, effect of GH and IGF-1 on DNA synthetic activity of thymocytes was examined. By 48-hrs. culture with IGF-1 and 24-hrs. 3H-TdR pulse labeling, significant enhancement of DNA synthetic activity of thymocytes was detected, while the enhancement in the culture with GH was very weak. It is considered that IGF-1 acts on the cells in G0/G1 phase in cell cycle. The effect of IGF-1 on thymocyte proliferation was examined by using the thymocytes incubated 12 hrs. before IGF-1 stimulation and 3-hrs. 3H-TdR pulse labeling. The optimal condition to induce thymocyte proliferation was 15-hrs. culture with 380 ng/ml of IGF-1. Furthermore, 10 ng/ml or higher concentration of GH significantly increases IGF-1 release from TECs in confluent state. These results suggest that GH indirectly participates in thymus growth by increasing IGF-1 release from TECs, which enhances thymocyte proliferation.
Cell Mol Biol (Noisy-le-grand) 1994 Mar
PMID:The indirect participation of growth hormone in the thymocyte proliferation system. 800 42

Intracellular pathways mediating feedback regulation by insulin-like growth factor-1 (IGF-1) of pituitary GH gene expression remain incompletely understood. Extracellular signal-related kinases (ERKs), a family of serine/threonine kinases, are activated by tyrosine kinase-associated growth factor receptors. To further define the IGF-1 postreceptor events occurring in GH-secreting cells, we investigated the activity of ERKs in response to IGF-1 in GC cells following stable transfection with either wild type human IGF-1 receptor cDNA (WT cells) or a mutant cDNA encoding a truncated, kinase-defective IGF-1 receptor with a dominant negative effect on endogenous receptor function (952STOP cells). Zymography of immunoprecipitated ERKs in myelin basic protein (MBP)-containing polyacrylamide gels demonstrated dose-dependent induction of ERK-1 and -2 activity by IGF-1 in GC cells with maximal activity occurring at 6 min. IGF-1-induced ERK activity in WT-transfected cells was up to 80-fold basal and 4-fold that observed in GC cells. 952STOP cells expressing the tyrosine kinase-deficient receptor were refractory to IGF-1 action, demonstrating minimal ERK induction. In contrast, 12-O-tetradecanoylphorbol 13-acetate stimulated ERK activity to the same degree in all three cell types regardless of their IGF-I receptor status. Forskolin (50 microM), isobutylmethylxanthine (0.5 mM), and forskolin/isobutylmethylxanthine in combination attenuated IGF-1-induced ERK activity in WT cells by 54, 55, and 75% respectively. The rapid, dose-dependent, and IGF-1 receptor-dependent activation of ERKs and the attenuation of this effect by cAMP suggest an interrelated role for both molecules in IGF-1 signal transduction in GH-secreting cells.
Mol Endocrinol 1994 May
PMID:Insulin-like growth factor-1 activation of extracellular signal-related kinase-1 and -2 in growth hormone-secreting cells. 805 64


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