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PubMed1991

Effect of DMBA on the expression of prolactin receptors and IGF1 genes in rat mammary gland.

Prolactin receptor and IGF1 gene expression were measured in mammary glands from Sprague-Dawley rats at different times (10, 30; and 58 d) after administration of a single dose of 15 mg dimethylbenz(a)-anthracene (DMBA) per os at 55 d of age, and in DMBA-induced mammary tumors appearing in these rats at approximately 2 months after DMBA administration; The relative gene expression of prolactin receptor and insulin-like growth factor (IGF1) mRNAs was measured by hybridization to Northern blots prepared from pools of tissue. The probes used were 32P-labelled cDNAs specific to the extracellular domain of the receptor (E probe), common to all forms, and a probe specific to the intracellular position of the long form of the receptor (I probe), a human IGF1 probe, and chicken beta-actin probe, to correct for loss of tissue and different metabolic activity of the tissues. Hybridization with the prolactin receptor probes revealed bands at 2.5, 3; and 5.5 kb hybridizing with the long form of the receptor and a more intense band at 1.8 kb that corresponded to the short form of the receptor. There were no changes in the relative expression of prolactin receptor mRNAs in the mammary gland of control (oil-treated) or DMBA-treated rats, although there was a gradual diminution of expression with increasing age of the animals. In contrast, in DMBA-induced mammary tumors, there was a marked increase in the relative expression of prolactin receptor mRNAs with, however, no modification in the relative proportion of short and long forms.(ABSTRACT TRUNCATED AT 250 WORDS)

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2005

Interactions between CCAAT enhancer binding protein delta and estrogen receptor alpha control insulin-like growth factor I (igf1) and estrogen receptor-dependent gene expression in osteoblasts.

Although ambient levels of estradiol and synthesis of the osteoblast growth factor IGF-I are inversely related in vivo, estradiol has little or no direct effect on igf1 gene expression in rat osteoblasts in vitro. Rather, estradiol suppresses the effect of hormones that enhance igf1 expression through protein kinase A dependent activation of CCAAT enhancer binding protein (C/EBP) transcription factors. We show here that inhibition of C/EBP activity by estradiol relates to the level of estrogen receptor alpha (ERalpha) expression, and that a complex between hormone-activated ERalpha and C/EBPdelta inhibits transcription by each factor. Protein fragmentation, co-immunoprecipitation, and gene expression studies identified domains for physical and functional interactions between ERalpha and C/EBPdelta. Whereas ERalpha and fragments comprising its various domains associated with C/EBPdelta, only ERalpha fragment A/B alone replicated the suppressive effect of intact ERalpha on endogenous C/EBPdelta activity. Complementary studies showed that several carboxyl regions of C/EBPdelta cooperatively inhibit ERalpha dependent transcription. Therefore, multiple domains of C/EBPdelta and ERalpha can physically interact to alter gene expression in osteoblasts in selective ways that depend on variations in the local hormone environment. Their combined effects on one important gene target, igf1, may help to determine the balance in the overall rates of bone formation.

Animals↗

PubMed1990

Modulation of sulfated proteoglycan synthesis and collagen gene expression by chondrocytes grown in the presence of bFGF alone or combined with IGF1.

Prepubertal rabbit epiphyseal chondrocytes were grown in high density primary culture for 3 d. They were then incubated for 3 additional d in serum-free culture medium to which bFGF (1-50 ng/ml) was added. During the last 24 h incubation period, either IGF1 (1-80 ng/ml) or Insulin (1-5 micrograms/ml) was added to the culture medium. Chondrocyte DNA was significantly augmented with the increasing concentration of bFGF used, thus confirming its mitogenic effect on chondrocytes. On the other hand, bFGF was also shown to modulate the phenotypic expression of the chondrocytes. The 35S-sulfate incorporation into newly synthesized proteoglycans by the cultured cells decreased in a dose-dependent manner with bFGF concentration used. In addition, chondrocyte collagen gene expression was also shown to be modulated by bFGF. Total RNA extracted from the cultured cells was analyzed by dot blot and Northern blot with cDNA probes encoding for alpha 1 II and alpha 1 I procollagen chains. A significant lower level of type II collagen mRNA, the marker of chondrocytic phenotype, was observed when cells were grown in the presence of bFGF while the level of type I mRNA remained unchanged. When IGF1 or a high concentration of insulin was added to the cells during the last 24 h of incubation with bFGF, sulfated proteoglycan synthesis, as well as collagen type II mRNA level, were significantly stimulated when compared with chondrocytes incubated with bFGF alone. In conclusion, in the present experimental conditions, bFGF appears to be a growth promoting agent for chondrocytes in vitro with dedifferentiating action on chondrocyte phenotype. IGF1 or insulin used at a high concentration can prevent the dedifferentiating effect of bFGF without inhibiting its stimulating effect on chondrocyte DNA synthesis.

Animals↗

PubMed2006

IGF1 gene polymorphism and risk for hereditary nonpolyposis colorectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder caused by germline mutations in DNA mismatch repair (MMR) genes. Insulin-like growth factor-I (IGF-I) is involved in colorectal carcinogenesis, and elevated plasma IGF-I levels are associated with sporadic colorectal cancer (CRC) risk. We investigated the relationship between IGF1 promoter cytosine-adenine (CA) dinucleotide-repeat polymorphism length and CRC risk in 121 MMR gene mutation carriers using Cox regression and Kaplan-Meier analysis. All statistical tests were two-sided. Time to onset for CRC increased for each decrease in CA-repeat number (median = 19 repeats, range = 12-22 repeats; hazard ratio [HR] = 1.17, 95% confidence interval [CI] = 1.05 to 1.31; P = .006). Patients carrying a CA(< or = 17) repeat allele had a statistically significantly higher CRC risk (HR = 2.36; 95% CI = 1.28 to 4.36; P = .006) than all others and were younger at onset (44 years versus 56.5 years; P = .023). These findings indicate a statistically significant association between shorter IGF1 CA-repeat lengths and increased risk for CRC in HNPCC. This is the first report, to our knowledge, to show that IGF1 variant genotypes modify risk of a hereditary form of cancer.

Adenine↗

PubMed2005

Effects of polymorphic microsatellites in the regulatory region of IGF1 and GHR on growth and carcass traits in beef cattle.

Growth hormone (GH), insulin-like growth factors 1 and 2 (IGF1 and IGF2) and their associated binding proteins and transmembrane receptors (GHR, IGF1R and IGF2R) play an important role in the physiology of mammalian growth. The objectives of the present study were to estimate the allele and genotype frequencies of microsatellite markers located in the 5'-regulatory region of the IGF1 and GHR genes in beef cattle belonging to different genetic groups and to determine effects of these markers on growth and carcass traits in these animals under an intensive production system. For this purpose, genotyping was performed on 384 bulls including 79 Nellore, 30 Canchim (5/8 Charolais + 3/8 Zebu) and 275 crossbred animals originating from crosses of Simmental (1/2 Simmental, n = 30) and Angus (1/2 Angus, n = 245) sires with Nellore females. The effects of substituting L allele for S allele of GHR microsatellite across Nellore, Canchim and 1/2 Angus were significant for weight gain and body weight (P < 0.05). The IGF1 microsatellite allele substitutions of 229 for 225 within Nellore group and of 225 for 229 within 1/2 Angus were not significant for any of the traits.

Animals↗

PubMed2005

IGF1 (CA)19 repeat and IGFBP3 -202 A/C genotypes and the risk of prostate cancer in Black and White men.

We investigated the relationship between the insulin-like growth factor-1 (IGF1) cytosine-adenine repeat (CA)(19) polymorphism located upstream of the gene's transcription start site, the insulin-like growth factor binding protein-3 (IGFBP3) -202 A/C promoter region polymorphism, and prostate cancer risk in Black and White men. Study subjects were U.S. veterans ages 41 to 75 years identified at the Durham Veterans Administration Medical Center over a 2.5-year period. Controls (n = 93) were frequency matched to cases (n = 100) based on race (Black or White) and age. Multivariable unconditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for the associations between the polymorphisms and prostate cancer risk. For Blacks and Whites combined, an inverse association between prostate cancer and being homozygous for the most common IGF1 repeat allele, (CA)(19), (adjusted OR, 0.3; 95% CI, 0.1-0.7) was observed. Similar associations were noted for both Blacks (OR, 0.2; 95% CI, 0.0-0.8) and Whites (OR, 0.4; 95% CI, 0.1-1.6) separately. No statistically significant associations between the IGFBP3 C allele and prostate cancer were noted for Blacks (adjusted OR, 2.3; 95% CI, 0.8-6.2) or Whites (OR, 1.0; 95% CI, 0.3-3.1). The prevalence of the homozygous IGF1 (CA)(19) genotype was much lower in Black controls (21%) than White controls (46%), which may, in part, explain the increased prostate cancer incidence in Black versus White men. Further research is needed to confirm these findings.

Adult↗

PubMed2004

Associations among IRS1, IRS2, IGF1, and IGFBP3 genetic polymorphisms and colorectal cancer.

INTRODUCTION: Insulin, insulin-like growth factor (IGF), and IGF binding protein (IGFBP) are involved in cell growth and proliferation and are thought to be important in the etiology of colorectal cancer. We hypothesize that genetic polymorphisms of insulin receptor substrates (IRS-1 and IRS-2), IGF-I, and IGFBP-3 alter colorectal cancer risk because of their roles in the insulin-related signaling pathway. METHODS: Data from a population-based incident case-control study of 1,346 colon cancer cases and 1,544 population-based controls and 952 rectal cancer cases and 1,205 controls were used to evaluate associations. Genetic polymorphisms of four genes were investigated: an IGF1 CA repeat, the IGFBP3 -202 A > C, the IRS1 G972R, and the IRS2 G1057D. RESULTS: Having at least one R allele (GR or RR) for IRS1 G972R was associated with an increased risk of colon cancer [odds ratio 1.4, 95% confidence interval (95% CI) 1.1-1.9]. The IRS2 G972R heterozygote GD genotype significantly reduced risk of colon cancer (odds ratio 0.8, 95% CI 0.6-0.9). Neither the IGF1 nor the IGFBP3 variants was associated independently with colon cancer, but there was an association when examined with IRS1. Individuals with an IRS1 R allele and IGF1 non-192 allele were at a 2-fold increased risk of colon cancer (95% CI 1.2-4.4). There was a 70% (95% CI 1.02-2.8) increased risk of colon cancer with an IRS1 R allele and the IGFBP3 AC or CC genotype. The IRS2 GD genotype reduced risk of colon cancer, except among those with an IRS1 R allele. No significant associations were seen in analyses of main effects or interactions of these variants and rectal cancer risk. CONCLUSIONS: Both IRS1 and IRS2 variants were associated with colon cancer risk independently. Associations were slightly stronger when polymorphisms in multiple genes were evaluated in conjunction with other genes rather than individually. These data suggest that the insulin-related pathway may be important in the etiology of colon cancer but not rectal cancer.

Adult↗

PubMed1994

Assignment of the gene for porcine insulin-like growth factor 1 (IGF1) to chromosome 5 by linkage mapping.

Investigation of published sequence data from the porcine insulin-like growth factor 1 (IGF1) gene, resulted in the detection of a microsatellite in the first intron of the gene. Polymerase chain reaction (PCR) primers flanking the (CA)19 repeat were constructed. Polymorphism and Mendelian segregation were documented in a three-generation pedigree and allele frequencies were determined in 74 unrelated animals from four different breeds. Seven alleles were encountered. Linkage analysis was performed in a large pedigree established for gene mapping. Linkage between the IGF1 microsatellite and an anonymous microsatellite marker, S0005, was detected. Furthermore, IGF1 and S0005 was found to be linked to the porcine submaxillary gland mucin (MUC) gene, previously assigned to chromosome 5. The results presented here extend the linkage group on pig chromosome 5 and are in accordance with conserved synteny between human chromosome 12, cattle chromosome 5, mouse chromosome 10 and pig chromosome 5.

Alleles↗

PubMed1998

Characterization of a microsatellite in the promoter region of the IGF1 gene in domestic horses and other equids.

Insulin-like growth factor 1 (IGF1) regulates growth and metabolic functions in vertebrates. A dinucleotide repeat sequence located at the promoter region of the IGF1 gene has been reported in several vertebrate species and may affect the control of the transcriptional activity of this gene. The genotypes of animals from seven horse breeds were determined in order to study the potential association of allelic forms of this microsatellite with adult body size differences found in domestic horses. Among these breeds, five alleles were found. Breed-specific differences in adult body size could not be attributed to the presence or absence of any of the alleles observed. In addition, animals representing five other equid species were typed. Examples of apparent species-specific alleles were found. However, overlapping polymorphic size ranges preclude this microsatellite from being an absolute identifier for species or hybrid status in equids. The polymorphisms found at this IGF1 locus are useful for synteny and linkage mapping.

Alleles↗

PubMed2005

Prostate cancer risk and IRS1, IRS2, IGF1, and INS polymorphisms: strong association of IRS1 G972R variant and cancer risk.

BACKGROUND: As cellular proliferation is central to the carcinogenic process, pathways that regulate proliferation may be important. Therefore, genes in the insulin and the insulin-like growth factor signaling pathways are plausible candidates for susceptibility genes for prostate cancer. We hypothesized that functional polymorphisms in INS, IRS1, IRS2, and IGF1 may be associated with prostate cancer. METHODS: We studied 199 incident prostate cancer cases and 267 age-matched controls. Genotyping was performed for the INS +1127 Ins-PstI, IRS1 G972R, IRS2 G1079D, and the IGF1 CA-repeat polymorphisms. Outcomes were prostate cancer, Gleason score, and AJCC stage. RESULTS: The IRS1 G972R GR/RR genotypes were associated with a significant 2.8-fold increased risk for prostate cancer (95% CI 1.5-5.1, P = 0.0007). The other variants were not significantly associated with prostate cancer. The IRS1 G972R GR/RR genotypes were also significantly associated with more advanced Gleason score (P = 0.001) and AJCC stage (P = 0.004). CONCLUSIONS: These results support a role of the insulin and/or insulin-like growth factor pathways in the etiology of prostate cancer.

Adult↗

PubMed2001

Large de novo deletion in chromosome 12 affecting the PAH, IGF1, ASCL1, and TRA1 genes.

Phenylketonuria is one of the most common genetic diseases in humans, affecting 1 in 10,000 whites. Deletions are generally uncommon in genes in which no long highly homologous segments are present, and in phenylalanine hydroxylase (PAH) deficiency they represent only 5% of cases. We present the case of a girl affected by classical phenylketonuria who has been screened for mutations in the PAH gene. During the molecular study a large de novo deletion has detected in 12qter, including PAH, and the genes for insulin-like growth factor 1 (IGF1), human achaete-scute homolog 1 (ASCL1), and tumor rejection antigen (TRA1). The patient showed phenylketonuria, short stature, and pathological electro-oculography results in both eyes, with high affectation of the relative electrogenesis of the photoreceptor-pigment epithelium complex. She had previously been misdiagnosed as homozygous for the IVS8nt-7A-G mutation, instead of heterozygous for a mutation and a de novo deletion. As a result incorrect genetic counseling had been given. The deletion of the PAH, IGF1, and ASCL1 genes could explain the patient's phenotype corresponding to a contiguous gene syndrome. We stress the relevance of polymorphic marker haplotype analysis and the importance of family study in genetic recessive diseases, such as phenylketonuria, to avoid incorrect diagnosis and genetic counseling.

Antigens, Neoplasm↗

PubMed2001

The BPS domain of Grb10 inhibits the catalytic activity of the insulin and IGF1 receptors.

Grb7, Grb10 and Grb14 comprise a family of adaptor proteins that interact with numerous receptor tyrosine kinases upon receptor activation. Between the pleckstrin homology (PH) domain and the Src homology 2 (SH2) domain of these proteins is a region of approximately 50 residues known as the BPS (between PH and SH2) domain. Here we show, using purified recombinant proteins, that the BPS domain of Grb10 directly inhibits substrate phosphorylation by the activated tyrosine kinase domains of the insulin receptor and the insulin-like growth factor 1 (IGF1) receptor. Although inhibition by the BPS domain is dependent on tyrosine phosphorylation of the kinase activation loop, peptide competition experiments indicate that the BPS domain does not bind directly to phosphotyrosine. These studies provide a molecular mechanism by which Grb10 functions as a negative regulator of insulin- and/or IGF1-mediated signaling.

Amino Acid Sequence↗

PubMed2002

Structural biology of insulin and IGF1 receptors: implications for drug design.

Type 2 diabetes mellitus -- in which the body produces insufficient amounts of insulin or the insulin that is produced does not function properly to control blood glucose -- is an increasingly common disorder. Prospective clinical studies have proven the benefits of tighter glucose control in reducing the frequency and severity of complications of the disease, leading to the advocation of earlier and more aggressive use of insulin therapy. Given the reluctance of patients with type 2 diabetes to inject themselves with insulin, orally active insulin mimetics would be a major therapeutic advance. Here, we discuss recent progress in understanding the structure-function relationships of the insulin and insulin-like growth factor 1 (IGF1) receptors, their mechanism of activation and their implications for the design of insulin-receptor agonists for diabetes therapy and IGF1-receptor antagonists for cancer therapy.

Animals↗

PubMed2005

JAK1 and Tyk2 activation by the homologous polycythemia vera JAK2 V617F mutation: cross-talk with IGF1 receptor.

The majority of polycythemia vera (PV) patients harbor a unique somatic mutation (V617F) in the pseudokinase domain of JAK2, which leads to constitutive signaling. Here we show that the homologous mutations in JAK1 (V658F) and in Tyk2 (V678F) lead to constitutive activation of these kinases. Their expression induces autonomous growth of cytokine-dependent cells and constitutive activation of STAT5, STAT3, mitogen-activated protein kinase, and Akt signaling in Ba/F3 cells. The mutant JAKs exhibit constitutive signaling also when expressed in fibrosarcoma cells deficient in JAK proteins. Expression of the JAK2 V617F mutant renders Ba/F3 cells hypersensitive to insulin-like growth factor 1 (IGF1), which is a hallmark of PV erythroid progenitors. Upon selection of Ba/F3 cells for autonomous growth induced by the JAK2 V617F mutant, cells respond to IGF1 by activating STAT5, STAT3, Erk1/2, and Akt on top of the constitutive activation characteristic of autonomous cells. The synergic effect on proliferation and STAT activation appears specific to the JAK2 V617F mutant. Our results show that the homologous V617F mutation induces activation of JAK1 and Tyk2, suggesting a common mechanism of activation for the JAK1, JAK2, and Tyk2 mutants. JAK3 is not activated by the homologous mutation M592F, despite the presence of the conserved GVC preceding sequence. We suggest that mutations in the JAK1 and Tyk2 genes may be identified as initial molecular defects in human cancers and autoimmune diseases.

Cell Line, Tumor↗

PubMedDate not supplied

Genetic and physical mapping of the chicken IGF1 gene to chromosome 1 and conservation of synteny with other vertebrate genomes.

The chicken insulin-like growth factor 1 gene has been assigned to the short arm of chromosome 1 near the centromere by fluorescence in situ hybridization and genetic linkage analysis. Comparison of physical and genetic linkage maps locates the centromere between the IGF1 and GAPD loci. Comparison of the genetic maps of chicken and other vertebrates reveals a highly conserved syntenic group, including the GAPD-IGF1 loci.

Animals↗

PubMed2004

Insulin resistance and changes in plasma concentration of TNFalpha, IGF1, and NEFA in dogs during weight gain and obesity.

Obesity-induced insulin resistance (IR) is a common problem in humans as well as domestic dogs. It is well-known that this syndrome is associated with many modifications but it is still unclear if the changes are alterations or adaptations. The purpose of this study was to develop obesity-induced IR in dogs, through a long-term overfeeding period, and to explore hormonal and metabolic disturbances associated with the development of this syndrome. Dogs were overfed for 7 months. Body weight increased by 43 +/- 5%, and insulin sensitivity decreased by 44 +/- 5%. Plasma insulin-like growth factor 1 (IGF1), tumour necrosis factor alpha (TNFalpha), and non-esterified fatty acids (NEFA) concentrations progressively increased during the overfeeding period (IGF1: 111 +/- 13 to 266 +/- 32 ng/ml, p < 0.001; TNFalpha: 5 +/- 5 to 134 +/- 41 pg/ml; NEFA: 0.974 +/- 0.094 to 1.590 +/- 0.127 mmol/l, p < 0.05). These metabolic and hormonal impairments are associated with IR, in obese dogs, and could explain, at least in part, the outbreak of this syndrome.

Animals↗

PubMed1994

Comparative analysis of TGF beta s, BMPs, IGF1, msxs, fibronectin, osteonectin and bone sialoprotein gene expression during normal and in vitro-induced odontoblast differentiation.

Immobilized TGF beta 1 and BMP2 are able to promote the differentiation of odontoblast-like cells in isolated mouse dental papillae cultured in vitro. These cells polarize and accumulate predentin-like matrix at their apical pole. Immobilized IGF1 mainly promoted polarization with disturbed matrix accumulation. In situ hybridization demonstrated that TGF beta 1 combined with heparin mirrored the physiological processes of odontoblast differentiation. Normal odontoblast and in vitro induced odontoblast-like cells expressed transcripts encoding for TGF beta 1 and 3, BMP2 and 4, bone sialoprotein and osteonectin whereas either ubiquitous expression or no expression could be detected for TGF beta 2, IGF1 or fibronectin mRNAs. Odontoblast-like cells obtained in the presence of IGF-1 combined with heparin did not express TGF beta 1 transcripts and expressed weakly TGF beta 3 transcripts. Our results suggest that in vivo an epithelial-derived member of the TGF beta family trapped by basement membrane-associated components interacts with competent preodontoblasts and promotes the polarization by triggering the transcription of growth factor gene(s) like TGF beta itself and/or selector gene(s) like msx2.

Animals↗

PubMed1994

Growth hormone and IGF1 profile in short children with osteopetrosis.

Osteopetrosis is commonly associated with short stature. To identify the cause, 8 children with osteopetrosis and short stature were studied. One showed evidence of renal tubular acidosis, none showed evidence of anaemia, and all were clinically and biochemically euthyroid. Growth hormone profile was assessed using night sampling (8 patients), growth hormone provocative testing using insulin-induced hypoglycaemia (6 patients), and L-dopa-propranolol (8 patients). The mean nocturnal growth hormone values taken at 60 and 90 min after onset of sleep and at 4 a.m. were 5.5, 12.8, and 11.5 mu/L respectively. The peak stimulated growth hormone mean values with the insulin-induced hypoglycaemia (glucose 1.6-3.0 mmol/L, mean = 2.2) was 14 mu/L (range 7.3-24.5 mu/L) and with the L-dopa-propranolol was 25.6 mu/L (range 12.3-49 mu/L). IGF1 levels taken at 0 and 120 min of insulin-induced hypoglycaemia (0 min for L-dopa-propranolol), and at 120 min of L-dopa-propranolol, showed normal values for age. We conclude that: (1) growth hormone profiles in these children are normal; (2) tissue unresponsiveness to growth hormone and/or IGF1 is not likely to be the cause of short stature in children with osteopetrosis; and (3) osteopetrosis per se is not an indication for assessment of growth hormone status.

Adolescent↗