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Query: UNIPROT:P06889 (Mol)
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We have used differentiated L6 myocytes to investigate the regulation of glucose transporter gene expression by insulin and insulin-like growth factor-1 (IGF-1). Chronic exposure to insulin (1 microM) or IGF-1 (10 nm) resulted in a 2- to 5-fold stimulation of 3H-2-deoxy-D-glucose uptake and a corresponding increase in the expression of rat brain/HepG2-type glucose transporter mRNA (GTmRNA) and immunoreactive transporter protein. The dose responses to both insulin and IGF-1 for stimulation of glucose uptake were paralleled by the expression of GTmRNA. Glucose uptake and GTmRNA levels were half maximally stimulated by 350 and 100 nM insulin, respectively, or by 2 nM IGF-1. Comparison of receptor occupancy with stimulation of glucose uptake and GTmRNA expression suggests that insulin exerts its effects through the IGF-1 receptor. Fibroblast growth factor, epidermal growth factor, platelet-derived growth factor, and phorbol ester had little or no effect on GTmRNA expression. These results demonstrate that the IGF-1 receptor mediates chronic regulation of transporter mRNA expression and protein synthesis and activity in cultured rat muscle cells.
Mol Endocrinol 1989 Dec
PMID:Chronic stimulation of glucose transporter gene expression in L6 myocytes mediated via the insulin-like growth factor-1 receptor. 256 Aug 11

Protein and cDNA sequence analysis have revealed that the insulin-like growth factor (IGF-I) has been highly conserved among several mammalian species. Using the combined techniques of polymerase chain reaction and molecular cloning, we have now obtained the cDNA sequence encoding preproIGF-I from a teleost species, Oncorhynchus kisutch (coho salmon). The 2020 nucleotide (nt) cloned cDNA sequence contains a 528 nt open reading frame encoding 176 amino acids in preproIGF-I and 175 nt and 1317 nt of flanking 5'- and 3'-untranslated regions, respectively. The deduced amino acid sequence of salmon IGF-I is highly conserved relative to its mammalian homologues and there are only 14 amino acid differences out of 70 between salmon and human IGF-I. Interestingly, the C-terminal E domain of salmon proIGF-I, which is presumed to be proteolytically cleaved during biosynthesis, also shows striking amino acid sequence homology with its mammalian counterpart, except for an internal 27 residue segment that is unique to salmon proIGF-I. Northern analysis revealed that salmon preproIGF-I mRNA consists predominantly of a single 3900 nt sized band although minor bands were also observed after prolonged autoradiographic exposure. The RNA analysis also revealed that the level of preproIGF-I mRNA is increased 6-fold in liver RNA isolated from salmon injected with bovine GH, as compared to untreated controls. These results demonstrate that the primary structure and regulated expression of IGF-I by GH have been conserved in teleosts.
Mol Endocrinol 1989 Dec
PMID:Nucleotide sequence and growth hormone-regulated expression of salmon insulin-like growth factor I mRNA. 262 35

Phorbol esters bind to and activate a family of Protein Kinase C (PKC) proteins, although the degree to which the various PKC forms mediate specific biological functions is unknown. We and others have previously shown that, after exposure to phorbol esters, cultured fibroblasts exhibit increased expression of the mRNA encoding the HepG2/brain glucose transporter (GT mRNA). We therefore studied phorbol ester regulation of GT mRNA in rat fibroblasts which do (R6-PKC3) or do not (R6-C1) stably overproduce a full-length cDNA encoding the PKC beta 1 isotype. When PKC beta 1 is overproduced in a cell that normally has undetectable levels, it is capable of increasing HepG2/brain GT mRNA in response to alpha-D-glucose phorbol 12-myristate 13-acetate (TPA). The level of GT mRNA is maximally induced 6 to 8-fold over basal levels 6 h after exposure to TPA (10 ng/ml) in R6-PKC3 cells that overproduce PKC beta 1, but only 2-fold over basal levels in the control R6-C1 cells. This TPA induced increase in the level of GT mRNA was observed as early as 1 h, peaked by 6-8 h and decreased markedly by 24 h in both cell types. The effect of PKC beta 1 on GT mRNA expression is probably mediated through enhancement of transcription, since the stability of GT mRNA was only minimally affected by TPA. Unlike the enhancement of TPA induced GT mRNA expression caused by overexpression of PKC beta 1, the responses of GT mRNA to calf serum, platelet-derived growth factor, epidermal growth factor, insulin or insulin-like growth factor-1 were the same in both cell types. After pretreatment with 1000 ng/ml TPA in 0.5% calf serum for 24 h, PKC activity was down-regulated and both R6-C1 and R6-PKC3 cells showed complete down-regulation of the GT mRNA responses to an additional treatment with 1000 ng/ml TPA. In contrast to the marked loss of responsiveness to TPA and PKC down-regulation, the responses of GT mRNA to serum, PDGF, EGF, insulin and IGF-1 were unaffected by down-regulation. Thus, our results provide direct evidence for both PKC-dependent and independent pathways regulating GT gene expression. Furthermore, it appears that the level of PKC beta 1 production, rather than down-stream signal transduction events, is the rate-limiting step in the pathway by which TPA induces an increase in GT mRNA.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Endocrinol 1989 Dec
PMID:Overproduction of the beta 1 form of protein kinase C enhances phorbol ester induction of glucose transporter mRNA. 262 36

Erythroleukemia cells (K562) were found to bind insulin-like growth factor-II (IGF-II) about 10 times as much as IGF-I, insulin and human growth hormone. The specific binding of IGF-II increased as a function of cell number in a range of 0.5-6 X 10(6) cell/ml. Kinetic studies revealed that binding was time and temperature dependent and showed a broad pH optimum. Specificity studies showed no inhibition of 125I-IGF-II binding by insulin or unrelated peptide hormones. The half-maximal inhibition of 125I-IGF-II binding to K562 cells was achieved at 87 and 28 ng/ml of IGF-I and IGF-II respectively. However, the addition of 7.5 and 1.7 ng/ml of unlabeled IGF-I and IGF-II respectively increased the binding of 125I-IGF-II by 55%. This 'hook' effect was greatly reduced when K562 cell membranes were used. Scatchard analysis of IGF-II binding showed a comparable equilibrium constant with either intact cells (Ka = 8.9 X 10(8) M-1) or microsomal membranes (Ka = 5.4 X 10(8) M-1). Cross-linking studies indicated that both 125I-IGF-II and 125I-IGF-I bound to an entity of 215 kDa which increased to 260 kDa under reducing conditions. Both IGF-I and II stimulated 3H-thymidine incorporation into K562 cells whereas insulin was without effect. These data show that both IGF-I and II bind predominantly to a type II-IGF receptor in K562 cells. Since both peptides stimulate 3H-thymidine incorporation in these cells it is possible that the type II-IGF receptor is mediating an anabolic biological response in these cells.
Mol Cell Endocrinol 1988 Apr
PMID:Characterization of the insulin-like growth factor (IGF) receptor in K562 erythroleukemia cells; evidence for a biological function for the type II IGF receptor. 296 13

The control of eucaryotic cell proliferation is governed largely by a series of regulatory events which occur in the G1 phase of the cell cycle. When stimulated to proliferate, quiescent (G0) 3T3 fibroblasts require transcription, rapid translation, and three growth factors for the growth state transition. We examined exponentially growing 3T3 cells to relate the requirements for G1 transit to those necessary for the transition from the G0 to the S phase. Cycling cells in the G1 phase required transcription, rapid translation, and a single growth factor (insulin-like growth factor [IGF] I) to initiate DNA synthesis. IGF I acted post-transcriptionally at a late G1 step. All cells in the G1 phase entered the S phase on schedule if either insulin (hyperphysiological concentration) or IGF I (subnanomolar concentration) was provided as the sole growth factor. In medium lacking all growth factors, only cells within 2 to 3 h of the S phase were able to initiate DNA synthesis. Similarly, cells within 2 to 3 h of the S phase were less dependent on transcription and translation for entry into the S phase. Cells responded very differently to inhibited translation than to growth factor deprivation. Cells in the early and mid-G1 phases did not progress toward the S phase during transcriptional or translational inhibition, and during translational inhibition they actually regressed from the S phase. In the absence of growth factors, however, these cells continued progressing toward the S phase, but still required IGF at a terminal step before initiating DNA synthesis. We conclude that a suboptimal condition causes cells to either progress or regress in the cell cycle rather than freezing them at their initial position. By using synchronized cultures, we also show that in contrast to earlier events, this final, IGF-dependent step did not require new transcription. This result is in contrast to findings that other growth factors induce new transcription. We examined the requirements for G1 transit by using a chemically transformed 3T3 cell line (BPA31 cells) which has lost some but not all ability to regulate its growth. Early- and mid-G1-phase BPA31 cells required transcription and translation to initiate DNA synthesis, although they did not regress from the S phase during translational inhibition. However, these cells did not need IGF for entry into the S phase.
Mol Cell Biol 1984 Sep
PMID:Post-transcriptional control of the onset of DNA synthesis by an insulin-like growth factor. 638 47

Insulin-like growth factor II (IGF-II)-overexpressing NIH 3T3 cells were used to examine regulation of insulin-like growth factor binding protein (IGFBP) and mannose 6-phosphate (M6P)/IGF-II receptor expression. Ligand blot analysis of conditioned media indicated a predominant IGFBP of 26-28 kilodaltons the abundance of which is 3- to 10-fold higher in media of IGF-II-overexpressing cells. The IGFBP level in control cell medium was increased by incubation in the presence of IGF-II, IGF-I, and mutant IGF-II forms with reduced affinities for IGF-I or M6P/IGF-II receptors. Further proof that IGF-II regulated the IGFBP was obtained by incubation of IGF-II overexpressing cells in the presence of antisense IGF-II oligomers or anti-IGF-II antibodies, which resulted in significant reduction of the IGFBP in conditioned medium. Mouse IGFBP-6 mRNA expression was increased in IGF-II-overexpressing or IGF-II-treated control cells. The IGFBP contained O-linked carbohydrate residues and was recognized by an antiserum to rat IGFBP-6. To determine whether IGFs were influencing proteolytic degradation of IGFBPs, cell-free conditioned media were incubated at 37 C with recombinant human IGFBPs. At neutral pH proteolysis of IGFBP-5 occurred during incubation in conditioned media from control and IGF-II-overexpressing cells. Upon acidification of the medium samples, only the degradation of IGFBP-6 was prevented in IGF-II-overexpressing cell-conditioned medium.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1995 Jul
PMID:Regulation of insulin-like growth factor (IGF)-binding protein-6 and mannose 6-phosphate/IGF-II receptor expression in IGF-IL-overexpressing NIH 3T3 cells. 747 72

Distribution of messenger RNA (mRNA) encoding the insulin-like growth factor (IGF) type 2 receptor (IGF2R) is investigated in the rat lower brainstem by in situ hybridization histochemistry. Cells with IGF2R mRNA are distributed widely in a region-specific manner. It is expressed in: (1) motor nuclei such as the oculomotor nucleus, trochlear nucleus, motor trigeminal nucleus, abducens nucleus, facial nucleus, ambiguus nucleus, dorsal motor nucleus of vagus and hypoglossal nucleus; (2) several sensory-related nuclei like the mesencephalic trigeminal nucleus, ventral nucleus of the lateral lemniscus, lateral and spinal vestibular nuclei, ventral and dorsal cochlear nuclei and nucleus of the trapezoid body; and (3) other regions such as the red nucleus, dorsal raphe nucleus, pontine nuclei, three cerebellar nuclei (medial, interposed and lateral), Purkinje cells, cells in the granular layer of the cerebellum, locus coeruleus, several areas of the reticular nucleus and area postrema.
Brain Res Mol Brain Res 1995 Aug
PMID:Regional distribution of messenger RNA encoding the insulin-like growth factor type 2 receptor in the rat lower brainstem. 749 52

Although the precise role of insulin-like growth factor binding proteins (IGFBPs) in ovarian physiology remains a matter of study, existing data suggest a possible antigonadotropic role in the context of follicular atresia. Given the above and the need for improved understanding of the regulation of ovarian IGFBPs, we have set out to explore the ability of IGF-I to modulate IGFBP levels in cultured rat granulosa cells. Specifically, granulosa cells (5 x 10(5) viable cells/dish) from immature (23-25 days old), estrogen-primed rats were cultured under serum-free conditions for 72 h in the absence or presence of IGF-I. At the conclusion of this incubation period, media samples were collected and subjected to Western ligand blotting. Treatment with IGF-I (100 ng/ml) resulted in a substantial (P < 0.05) increase in the accumulation of IGFBP-5, the major 28-29 kDa IGFBP species. Subsequent studies revealed this effect of IGF-I to be both dose- and time-dependent. A similar effect was noted for insulin at dose levels 1-10 micrograms/ml at which cross-reaction with the type I IGF receptor (but not with IGFBPs) has been amply documented. Des (1-3) IGF-I, a type I receptor-selective ligand with markedly reduced avidity for IGFBPs, proved substantially more potent (as a promoter of IGFBP-5 accumulation) than its native counterpart. In contrast, treatment with IGF-II or [Leu27]IGF-II, type II IGF receptor-selective ligands, yielded a more limited effect on IGFBP-5 accumulation in keeping with an overall rank order of potency of des (1-3) IGF-I > IGF-I > IGF-II > or = [Leu27]IGF-II.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1994 Mar
PMID:IGF-I stimulates granulosa cell-derived insulin-like growth factor binding protein-5: evidence for medication via type I IGF receptors. 751 41

The insulin-like growth factor binding proteins (IGFBPs) comprise a family of six distinct proteins which modulate insulin-like growth factor action. We have isolated cDNAs encoding the six mouse IGFBPs (mIGFBPs). In addition, we studied the mRNA expression of the six mIGFBPs during development and in various adult tissues. Our results show that each of the six mIGFBPs is highly homologous to their human and rat counterparts, whereas only the N and C terminal ends are conserved between the six mIGFBPs. Northern blotting revealed that mIGFBP-2, -3, -4 and -5 genes are already expressed at gestational day 11.5, suggesting a role for these mIGFBPs in embryonal development. In liver, a peak of mIGFBP-1 mRNA expression was found around birth, suggesting a function for mIGFBP-1 in the newborn mouse. Finally, tissue-specific expression of the six mouse IGFBP genes was observed in adult tissues suggesting different roles or modes of actions in adult life.
Mol Cell Endocrinol 1994 Aug
PMID:cDNA cloning and mRNA expression of the six mouse insulin-like growth factor binding proteins. 752 32

The results of this report provide evidence that insulin-like growth factor-1 binding proteins (IGFBPs) in human sera are differentially regulated as a result of severe burn injury. Using the ligand binding technique, 125I-IGF-1 visualizes 5 different protein bands corresponding to those previously reported for IGFBP-1 to 4 with apparent sizes of 23-42 kd in serum samples prepared from severely burned patients and healthy individuals. The level of IGFBP-3 was significantly decreased within 3-5 days of injury and remained depressed for up to 20 days post injury. The average level of this binding protein reached its lowest value within 3-5 days of the injury (3.8 +/- 1.48% relative to day 0-1 value, n = 4, p < 0.01). Serum samples from 3 of 4 patients showed no recovery within 20 days post injury and the level of IGFBP-3 remained significantly depressed (p < 0.01). In contrast, the levels of IGFBP-2 and IGFBP-4 increased 2 and 3 fold in the same serum samples within 3-5 days of the burn injury, respectively. This increase returns to normal (day 0-1 value) within 7-10 days for IGFBP-2, but the level of IGFBP-4 remained elevated 4 fold relative to the day 0-1 (p < 0.01). However, the abundance of IGFBP-1 in these serum samples was not significantly altered by the burn injury. By controlling for protein loading, these apparent alterations of IGFBPs in the sera of burned patients were not due to hemodilution. Similarly, significant reductions in IGFBP-3 were not likely due to IGFBP-3 specific protease activity in the sera of burn patients since incubation of sera from burn patients and normal individuals at 37 degrees C did not alter the pattern of IGFBPs in sera obtained from normal individuals. Of interest, the level of IGF-1 protein in these samples was also markedly reduced following severe burn injury similar to IGFBP-3. The results of this study suggest that a marked reduction of serum IGF-1 seen in burn patients is associated with a significant reduction of IGFBP-3, a major IGF-1 binding protein in human serum.
Mol Cell Biochem 1994 Jun 29
PMID:Differential effects of thermal injury on circulating insulin-like growth factor binding proteins in burn patients. 753 Aug 8


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