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A BglII RFLP at the ovine locus for insulin-like growth factor 1 (IGF1).
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Identification of a MaeI RFLP in the insulin-like growth factor-1 (IGF1) gene of swamp buffaloes (Bubalus b. bubalis kerebau).
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A novel mutation in a patient with insulin-like growth factor 1 (IGF1) deficiency.
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Minireview: tissue-specific versus generalized gene targeting of the igf1 and igf1r genes and their roles in insulin-like growth factor physiology.
The insulin-like growth factors (IGF-I and IGF-II) and the IGF-I receptor are critically important for normal growth and development of the organism. Gene-deletion of these elements has demonstrated that IGF-I is important for both prenatal and postnatal development, whereas IGF-II is important during prenatal stages only. The IGF-I receptor gene-deleted mouse dies at birth apparently as a result of poor muscular development. Utilizing the conditional gene-deletion approach, we have demonstrated that mice lacking the liver IGF-I gene have an approximately 80% reduction in circulating total IGF-I levels. Despite this marked reduction, postnatal growth and development was normal, suggesting that liver IGF-I is not essential for this function. Local tissue IGF-I production was unaffected and may compensate for the lack of the liver IGF-I. Further studies are ongoing to establish the role of the endocrine vs. the autocrine/paracrine IGF-I.
IGF1 receptor expression protects against microenvironmental stress found in the solid tumor.
The insulin-like growth factor 1 receptor (IGF1R) is a tyrosine kinase, transmembrane receptor expressed in most body tissues and required for normal growth of cells. In cell culture, overexpression of the receptor has been shown to promote transformation and enhance cell survival in response to selected cytotoxic agents. As tumors develop, abnormalities in vascularization lead to a heterogeneous environment that includes areas of hypoxia, low pH and low glucose. Here we report that the overexpression of the IGF1R promotes increased survival in cells exposed to hypoxia, low pH and low glucose. Furthermore, cells lacking the receptor due to targeted disruption of the IGF1R gene do not survive as well as normal cells in such conditions. In addition, we find that cells can activate the IGF1R gene promoter in response to these conditions, and immunoblot analyses show increased receptor protein levels in cell exposed to hypoxia. Our results suggest a pathway of cancer cell adaptation to the tumor microenvironment in which conditions of the environment may induce expression of IGF1R, and this subsequent overexpression of the receptor may increase cell survival in such conditions.
[Is aging associated with a diminution of insulin sensitivity? Roles of IGF1 and dehydroepiandrosterone].
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[Effect of IGF1 receptor gene antisense oligodeoxynucleotide on T24 urinary bladder cancer cells].
OBJECTIVE: To evaluate the effects of autocrine blockage on T24 urinary bladder cancer cells. METHODS: Semiquantitative RT-PCR, MTT determination, 3H thymidine incorporation, flow cytometry and electron microscopy were used to study the effects of antisense oligodexynucleotide (ODN) targeted against insulin-like growth factor 1 receptor (IGF1R) gene on IGF1R gene expression, drug sensitivity, proliferation and apoptosis of T24 cells. RESULTS: After being treated with antisense ODN specific for IGF1R gene for 48 hours, the intrinsic IGF1R mRNA expression of T24 cells reduced approximately by 72.9%, which caused decrease in survival and increased sensitivity to mitomycin-induced apoptosis(P < 0.05). CONCLUSION: To block the autocrine loop with IGF1R antisense oligonucleotide may serve as a potential therapeutic approach to bladder cancer.
[Mechanism of IGF1 receptor activation and signal transduction specificity].
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The downregulation of growth-associated proteins in motoneurons at the onset of synapse elimination is controlled by muscle activity and IGF1.
Axonal growth during development and regeneration coincides with the expression of growth-associated proteins (GAPs), including GAP-43 and tubulin-alpha 1. Following contact with the target region and synaptogenesis, GAPs are downregulated. However, high levels of GAP-43 are expressed in some neurons in the adult CNS, indicating that its function may not be restricted to axonal growth. To define the type of signals that regulate GAP levels during development, we have determined whether GAP downregulation coincides with a defined phase of synapse development and whether it is controlled by the postsynaptic target. Levels of GAP-43 mRNA in spinal motoneurons and protein at the neuromuscular junction were analyzed in the developing neuromuscular system of chick and rat. In both species, GAP-43 mRNA declined rapidly at a time corresponding to the onset of synapse elimination, and nerve terminal GAP-43 immunoreactivity became undetectable with a delay of 2-3 d. In rat motoneurons, GAP-43 and tubulin-alpha 1 mRNA levels declined with a similar time course, indicating that at least two GAPs are downregulated at the same time. Blockade of neuromuscular transmission with either a pre- or a postsynaptically acting toxin prevented GAP downregulation, indicating that target activity affects GAP mRNA levels in motoneurons. Finally, counteracting the activity-dependent decline of muscle insulin-like growth factors during synapse elimination by local subcutaneous injections prevented motoneuron GAP downregulation, suggesting that these growth factors may be involved in the regulation of motoneuron GAPs by the muscle. These results demonstrate that motoneurons undergo target-sensitive changes in GAPs at the onset of synapse elimination. In addition, these results raise the possibility that termination of a presynaptic growth mode may be a prerequisite for synapse elimination.
Insulin like growth factor I (IGF1) in children with neural tube closure defects: a preliminary report.
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Insulin and IGF1 receptor function among type II diabetic responders and nonresponders to glyburide.
This study evaluated the insulin and insulin-like growth factor-1 (IGF-1) receptor function among patients with type II diabetes who did or did not respond to 1 month of treatment with the oral sulfonylurea agent glyburide. Patients with type II diabetes were initially placed on dietary treatment alone. Patients whose fasting plasma glucose level exceeded 9 mmol/L were enrolled in a prospective 1-month trial of oral glyburide. Clinical, laboratory, and receptor characteristics were assessed before and after glyburide therapy and were compared between the responders and non-responders as well as with matched nondiabetic control subjects. Of the 34 patients who participated in the study, 17 (50%) responded (fasting plasma glucose decreased to 7.8 mmol/L or by 30% from basal level) to the drug. There were no clinical parameters that could distinguish between patients responding and not responding to glyburide. Iodine 125-labeled insulin binding to intact erythrocytes tended to be higher among responders both before and after glyburide. However, the studies of specific insulin binding and insulin receptor tyrosine kinase activities of purified erythrocyte receptors could not distinguish between the two groups of patients with diabetes either before or after glyburide treatment. Compared with weight-matched nondiabetic controls, the erythrocyte insulin receptor tyrosine kinase activity in the patients with diabetes was significantly (by about 45%) decreased. Studies of the IGF-1 receptor likewise did not reveal differences between the two diabetic groups. In conclusion, one half of ambulatory patients with type II diabetes showed a satisfactory hypoglycemic response to a short-term glyburide treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Growth hormone insensitivity syndrome (Laron syndrome): main characteristics and effects of IGF1 treatment.
Growth hormone (GH) insensitivity is a pathological state characterized by a disturbance of the physiological relationship between GH secretion, synthesis of insulin-like growth-factor I (IGF-1) and the biological actions of GH. Laron syndrome, the prototype for GH insensitivity, is most often due to GH receptor deficiency. However, this syndrome is heterogeneous in terms of growth characteristics, bio-chemical features and, most importantly, genetic defects. Recent data have indicated that partial GH receptor deficiency could be involved in children with apparently idiopathic short stature. Laron syndrome, because of extreme growth deficiency and a lack of alternative treatment, was the first clinical situation in which recombinant human IGF-1 was used. IGF-1 accelerates growth rate in most patients, induces subtle modifications of the craniofacies and decreases fat mass. However, it is still too early to evaluate the long-term effects of IGF-1 on final height. Tolerance to the drug has been excellent in all reported trials. The major (but rare) side effects are transient intracranial hypertension and hypokalemia. Generalization of data obtained in Laron syndrome to other clinical situations should take account of the profound alterations in IGF-1 pharmacokinetics resulting from a deficiency in IGF-binding proteins.
Two SSCP alleles detected in the 5'-flanking region of bovine IGF1 gene.
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The intrahepatic biliary epithelium is a target of the growth hormone/insulin-like growth factor 1 axis.
BACKGROUND/AIMS: We evaluated the role and mechanisms by which the GH/IGF1 axis modulates cholangiocyte proliferation. METHODS: GH-receptors (GH-R), IGF1, IGFBP3 (binding protein 3), IGF1-R and receptor substrates (IRS) were evaluated in cholangiocytes of normal or bile duct-ligated (BDL) rat livers. The effects of GH and IGF1 on proliferation of normal quiescent cholangiocytes and the transduction pathways involved were investigated. RESULTS: IGF1, GH-R, IGF1-R, IRS-1/2 were expressed in normal cholangiocytes and overexpressed in cholangiocytes proliferating after BDL which also secrete IGF1 in a higher amount than normal cells. IGFBP3, which may counter-regulate IGF1 effects, was decreased in BDL cholangiocytes. IGF1 promoted cholangiocyte proliferation in association with overexpression of p-IGF1R, IRS1, IRS-2, p-ERK1/2 and p-AKT. GH induced IGF1 expression and release in isolated cholangiocytes, and reproduced the effects of IGF1 but GH effects were abolished by IGF1-R blocking antibody, suggesting IGF1 as a mediator of GH. Finally, IGF1 and 17beta-estradiol reciprocally potentiated their proliferative effects on cholangiocytes, and by interacting at both receptor and post-receptor levels. CONCLUSIONS: Cholangiocytes respond to GH with production and release of IGF1 that modulates cell proliferation by transduction pathways involving IGF1-R, IRS1/2 and both ERK and PI3-kinase pathways. The biliary epithelium is a target of GH/IGF1 liver axis.
Insulin-like growth factor 1 receptor activates c-SRC and modifies transformation and motility of colon cancer in vitro.
Colorectal carcinomas have been found to express increased levels of IGF1 and IGF1-R, as compared to normal or adenomatous colonic mucosa, and it has been postulated that a subset of colorectal cancers are under the autocrine regulation of the IGF1/IGF1-R system. In this study, we selected human colorectal carcinoma cell lines with high (SW620, HT29, L4A) and low (CaCo2, and HCT 116) expression of IGF1-R by flow cytometry. Compared to the IGF1-R(-) cells, the IGF1-R(+) cells revealed a more aggressive phenotype as demonstrated by a higher proliferation rate (approximately 2-fold increase) in response to IGF1, higher degree of transformation (approximately 5-to-15-fold increase in colony formation in soft agar), increased resistance to serum deprivation-induced apoptosis [1-7 apoptotic cells/5 microscopic fields, as compared to 37 to 101 apoptotic cells/5 microscopic fields of the IGF1-R(-) cells], and higher migratory capability measured by a wounding assay [IGF1-R(+) cells migrated a distance of up to 15 millimeters from the cut edge of the monolayer, while the IGF1-R(-) cells were able to migrate only 2-3 millimeters away from the same reference point]. While the cell lines overexpressing the IGF1-R had higher levels of Src activation, the use of a Src inhibitor reduced the IGF1-R protein expression, slowed down the proliferation of IGF1-R(+) cells, and reduced their colony formation in soft agar. Based on the above observations, we conclude that an overexpressed and activated IGF1-R may increase the degree of transformation and motility of colon cancer cells by activating c-Src.
Insulin-like growth factor 1 receptors in human breast cancer and their relation to estradiol and progesterone receptors.
Insulin-like growth factor 1 (IGF1) binding sites were characterized in breast cancer. We demonstrate the presence of one high affinity binding site. Chemical cross-linking of 125I-IGF1 to breast cancer membranes in reducing condition and sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed one band with an apparent molecular weight of 130,000. The specificity of the binding was studied. IGF2 was a good competitor whereas insulin competed with a potency lower than 1/100 that of IGF1. This IGF1 binding corresponded to the previously described type 1 IGF receptor (IGF1-R). IGF1-R was determined in 76 human breast cancer biopsies. Ninety-three % of the tumors were positive. The specific binding range was 0-16.4%; the geometric IGF1-R mean level was 3.9%. There was a relation (chi 2 test) between IGF1-R and progesterone receptor positivity rates (P = 0.002). The IGF1-R concentrations were correlated (Spearman test) with those of estradiol receptor (P = 0.0018) and progesterone receptor (P = 0.0011). A positive linear correlation existed between IGF1-R and estradiol receptor (P = 0.006) and between IGF1-R and progesterone receptor (P = 0.003). Our demonstration of the presence of IGF1-R in human breast cancer biopsies suggests that IGF1, acting either via the endocrine, paracrine, or autocrine pathways, could stimulate tumor growth.
Biochemical and morphometric analyses show that myelination in the insulin-like growth factor 1 null brain is proportionate to its neuronal composition.
To elucidate the role of insulin-like growth factor 1 (IGF1) in the normal development of brain myelination, we used behavioral, biochemical, and histological analyses to compare the myelination of brains from Igf1(-/-) and wild-type (WT) littermate mice. The studies were conducted at postnatal day 40, at which time the Igf1(-/-) mice weighed approximately 66% less than wild-type mice. However, the Igf1(-/-) brain weight was only reduced by approximately 34%. Formal neurological testing showed no sign of central or peripheral myelinopathy in Igf1(-/-) mice. Myelin composition was not significantly different, and myelin concentration, normalized to brain weight or protein, was equal in Igf1(-/-) and WT mice. Likewise, concentrations of myelin-specific proteins (MBP, myelin proteolipid protein, MAG, and 2',3'-cyclic nucleotide,3'-phosphodiesterase) were not significantly different in Igf1(-/-) and WT mice. The myelin-associated lipids galactocerebroside and sulfatide were modestly reduced in Igf1(-/-) brains. Regional oligodendrocyte populations and myelin staining patterns were comparable in Igf1(-/-) and WT brains, with the notable exception of the olfactory system. The Igf1(-/-) olfactory bulb was profoundly reduced in size and was depleted of mitral neurons and oligodendrocytes, and its efferent tracts were depleted of myelin. In summary, this study shows that myelination of the Igf1(-/-) brain is proportionate to its neuronal composition. Where projection neurons are preserved despite the deletion of IGF1, as in the cerebellar system, oligodendrocytes and myelination are indistinguishable from wild type. Where projection neurons are depleted, as in the olfactory bulb, oligodendrocytes are also depleted, and myelination is reduced in proportion to the reduced projection neuron mass. These data make a strong case for the primacy of axonal factors, not including IGF1, in determining oligodendrocyte survival and myelination.