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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estrogen responses of human breast cancer cell lines have frequently been shown to be promoted by insulin. We have examined the action of insulin, and its interaction with estradiol, in regulating the expression of the estrogen-induced genes, LIV-1 and pS2. Both hormones cause increases in mRNA levels of the two genes but do so by distinct mechanisms. The concentration of insulin required to produce this effect suggests that it is acting via its ability to bind to the IGF-1 receptor. Both insulin and estradiol exert their effects at the level of transcription. Induction by insulin is dependent upon continued protein synthesis whereas induction by estradiol is not. Induction by both insulin and estradiol is prevented by the pure antiestrogen. ICI 164384, indicating the requirement for an activatable estrogen receptor. Insulin does not stimulate LIV-1 expression via the androgen receptor. These results demonstrate that both estradiol and insulin can stimulate the transcription of these estrogen-inducible genes, by separate mechanisms both of which involve the estrogen receptor.
Mol Cell Endocrinol 1996 Jul 23
PMID:Insulin/IGF-1 modulation of the expression of two estrogen-induced genes in MCF-7 cells. 886 63

In ovine pars tuberalis cells which express high affinity Mel 1a melatonin receptors, the ability of melatonin to directly stimulate or inhibit AP-1 transcription factor gene expression was studied. Effects of melatonin upon mRNA expression by forskolin, serum and IGF-1 were also investigated. Northern analysis showed melatonin had no direct stimulatory nor inhibitory effect upon transcription or translation. Melatonin was able to significantly inhibit forskolin-stimulated induction of c-fos and jun B mRNA whilst forskolin had no effect upon c-jun or jun D. Induction of c-Fos translation by forskolin was also inhibited by melatonin. Serum induced c-fos and c-jun, but melatonin was unable to affect these changes. Similarly IGF-1 stimulated c-fos and melatonin had no effect upon this induction. From these results it can be concluded that melatonin has no independent effects on expression of the AP-1 genes, rather its primary function is to inhibit cell activities through cyclic AMP-dependent routes of gene activation.
Mol Cell Endocrinol 1996 Oct 14
PMID:Melatonin suppresses the induction of AP-1 transcription factor components in the pars tuberalis of the pituitary. 891 13

Signal transduction by insulin and IGF-1, several interleukins (IL-2, IL-4, IL-9, IL-13), interferons, GH, and other cytokines involves IRS proteins, which link the receptors for these factors to signaling molecules with Src homology-2 domains (SH2-proteins). We recently reported the amino acid sequence of murine IRS-2; in order to examine a potential genetic role for this molecule in disease, we isolated the murine IRS-2 gene and compared the expression pattern of IRS-2 against IRS-1. Like IRS-1, IRS-2 is encoded by a single exon. Whereas IRS-1 is located on murine chromosome 1, IRS-2 is located on murine chromosome 8 near the insulin receptor. IRS-2 is expressed together with IRS-1 in many cells and tissues; however, IRS-2 predominates in murine hematopoietic cells where it may be essential for cytokine signaling; IRS-1 predominates in adipocytes and differentiated 3T3-L1 cells where it contributes to the normal insulin response. In 32D cells, IRS-1 and IRS-2 undergo differential tyrosine phosphorylation during insulin or IL-4 stimulation, as assessed indirectly by interaction with various recombinant SH2 domains. Thus, signaling specificity through the IRS proteins may be accomplished by specific expression patterns and distinct phosphorylation patterns during interaction with various activated receptors.
Mol Endocrinol 1997 Feb
PMID:The IRS-2 gene on murine chromosome 8 encodes a unique signaling adapter for insulin and cytokine action. 901 72

Myogenic regulatory factors (MRFs) promote differentiation of muscle cells from fibroblasts and are induced by insulin-like growth factor I (IGF-1). Prior studies have shown synthesis of new muscle protein and improved muscle morphology when mature dy mice with muscular dystrophy are treated with IGF-1. We investigated whether these salutary effects of IGF-1 might be attributable to stimulation of MRFs. Male dy (129ReJ) mice and controls (129J) were assigned to IGF-1 treatment (10 micrograms twice daily) or non-treatment at about 5 weeks of life and sacrificed 6 weeks later. RNA was extracted from skeletal muscles, reverse transcribed, and amplified by polymerase chain reaction (PCR) using primers specific for each MRF. Competitive PCR was performed to quantify MyoD expression in response to IGF-1 treatment. Transcripts for myf-5, MRF4, and myogenin were detected in both control and dy mouse muscles; no apparent differences were observed between treatment groups. Quantitative analysis of transcripts for MyoD indicated no significant basal differences between control and dy mice. There was, however, significantly higher MyoD expression in the dy group, and a trend toward significance in the control group, following IGF-1 treatment. These data suggest that IGF-1 exerts its in vivo effects in postembryonal muscle by stimulating MRFs.
Biochem Mol Med 1997 Apr
PMID:Expression of myogenic regulatory factors in normal and dystrophic mice: effects of IGF-1 treatment. 916 95

To understand the role of amylin, the novel pancreatic hormone, in fuel metabolism of neonatal mammals, the transcription of the amylin gene in newborn dogs was studied under different conditions, such as fasting, hyperinsulinemia, and hyper IGF-1. Our results showed (1) The amylin mRNA level decreased during a 24-h fasting period after birth, 59.1 +/- 4.5% at 4 h, 80.1 +/- 7.9% at 10 h, and 44.5 +/- 3.0% at 24 h, compared to 0-h-fasted controls, respectively. In this period, the decreased mRNA level of the amylin gene and the increased mRNA levels of the gluconeogenic genes showed an inverse ratio relationship. (2) Euglycemic hyperinsulinemic clamp did not alter the amylin mRNA level, 39.6 +/- 1.2% (hyperinsulinemia) vs 41.4 +/- 3.1% (controls), in newborn dogs, but lowered the amylin mRNA by 35.3%, 64.7 +/- 12.5% vs 100.0 +/- 12.0%, in adult dogs. (3) Euglycemic hyper-IGF-1 clamp had no effect on the amylin mRNA levels of either newborn or adult dogs, 52.4 +/- 9.1% (hyper IGF-1) vs 47.9 +/- 4.3% (controls) in newborns and 95.2 +/- 12.6% (hyper IGF-1) vs 100.0 +/- 14.0% (controls) in adults. The data from the present study showed that amylin may be involved in carbohydrate homeostasis, but may not be able to stimulate gluconeogenesis in newborn dogs during a 24-h fasting period after birth. Whether amylin action may be another mechanism for neonatal hyperglycemia by inducing insulin resistance in peripheral tissues needs further investigation.
Biochem Mol Med 1997 Aug
PMID:Transcription of the amylin gene in newborn dogs. 925 84

In a first series of experiments done in the yeast two-hybrid system, we investigated the nature of protein-protein interaction between the regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase), p55PIK, and several of its potential signaling partners. The region between the Src homology 2 (SH2) domains of p55PIK bound to the NH2 terminus region of p110alpha, as previously shown for p85alpha. Moreover, we found that the insulin-like growth factor-1 receptor (IGF-IR) bound to p55PIK; the interaction occurred at the receptor tyrosine 1316 and involved both p55PIK SH2 domains. Interaction between p55PIK and IGF-IR was seen not only in the yeast two-hybrid system, but also using in vitro binding and coimmunoprecipitation of lysates from IGF-1 stimulated 293 cells overexpressing p55PIK. Further, IGF-I stimulation of these cells led to tyrosine phosphorylation of p55PIK. In 293 cells association of p55PIK with insulin receptor substrate-1 and with IGF-IR was dependent on PI 3-kinase, since it was increased by wortmannin, an inhibitor of PI 3-kinase. Further, by deleting amino acids 203-217 of p55PIK inter-SH2 domain, we engineered a p55PIK mutant unable to bind to the p110alpha catalytic subunit of PI 3-kinase. This mutant had a dominant-negative action on insulin-stimulated glucose transport, since insulin's effect on Glut 4 myc translocation was inhibited in adipocytes expressing mutant p55PIK. Importantly, this dominant-negative mutant was more efficient than wild type p55PIK in associating to IGF-IR and insulin receptor substrate-1 in 293 cells. Taken together, our results show that p55PIK interacts with key elements in the IGF-I signaling pathway, and that these interactions are negatively modulated by PI 3-kinase itself, providing circuitry for regulatory feedback control.
Mol Endocrinol 1997 Dec
PMID:Interaction of wild type and dominant-negative p55PIK regulatory subunit of phosphatidylinositol 3-kinase with insulin-like growth factor-1 signaling proteins. 941 96

The effects of two vitamin D analogues, EB1089 and CB1093, on insulin-like growth factor binding protein (IGFBP) expression have been examined in MCF-7 and Hs578T human breast cancer cell lines. Both vitamin D analogues inhibited IGF-1 stimulated growth of MCF-7 cells and enhanced the production of IGFBP-3 as determined by Western-ligand blotting. Recombinant human IGFBP-3 inhibited the growth of MCF-7 cells over the concentration range 1-235 ng/ml. Hs578T cells were unresponsive to the mitogenic effects of IGF-1 but growth was inhibited by the two vitamin D analogues. Treatment of Hs578T cells with EB1089 and CB1093 (10 nM) as well as 100 nM 9-cis retinoic acid (9-cis RA) or all-trans retinoic acid (ATRA) was associated with increased accumulation of IGFBP-3 in conditioned medium. Furthermore, cotreatment of Hs578T cells with EB1089 and 9-cis RA led to augmented effects on both inhibition of cell growth and IGFBP-3 accumulation in conditioned medium as assessed by Western ligand blotting and radioimmunoassay. These findings suggest a role for IGFBP-3 in the growth inhibitory effects of vitamin D analogues.
J Mol Endocrinol 1998 Feb
PMID:Growth inhibition of both MCF-7 and Hs578T human breast cancer cell lines by vitamin D analogues is associated with increased expression of insulin-like growth factor binding protein-3. 951 92

We have monitored estrous cycle and measured serum estradiol, GH, IGF-1, T4 and T3 levels in adult hypothyroid female rats which were divided into four groups: H group, hypothyroid rats without treatment; H-T4 group, hypothyroid rats injected daily with T4; HT4-PTU group, hypothyroid rats injected daily with T4 plus PTU (propylthiouracil), and H-T4-IOP group, hypothyroid rats injected daily with T4 plus IOP (iopanoic acid); Euthyroid rats (E group) were used as control. Our results indicate that the lack of sexual cycle in H animals was associated with lower values of estradiol, GH and IGF-1 in comparison to E group; the restoration of sexual cycle in H-T4 group was associated with values of estradiol, GH and IGF-1 higher than those of H group, whereas in H-T4-PTU and H-T-IOP groups the restoration was associated with higher values of GH and IGF-1 and values of estradiol similar to those of H group. These data could suggest a potential role of GH/IGF-1 axis, at least in part, in the lack of sexual cycle in H group and in the ovulation induction in H-T4, H-T4-PTU and H-T4-IOP groups.
Mol Cell Biochem 1998 Feb
PMID:Possible role of GH/IGF-1 in the ovarian function of adult hypothyroid rats. 954 43

In mammalian cells, the insulin receptor substrate 1 protein (IRS-1) is a specific substrate for insulin and IGF-1 receptor tyrosine kinases which is involved in mediating metabolic and mitogenic actions of insulin and IGFs. In order to determine if IRS-1 is also essential in a chicken derived hepatoma cell line (LMH cells), IRS-1 gene has been invalidated in these cells. For this, we subcloned chicken IRS-1 gene in an antisense orientation into a mammalian expression vector driven by the cytomegalovirus early promoter. LMH cells were stably transfected with this construct or with the empty vector carrying only the neomycin resistance gene and selected for cIRS-1 expression. One subclone, C2, showed a complete repression of cIRS-1 expression at both protein and mRNA levels. Proliferation of C2 cells was dramatically reduced (54%) compared with Neo(r) cells. Furthermore this reduction was accompanied by a decrease in insulin-dependent [3H]thymidine incorporation, indicating a reduction in DNA synthesis. Insulin-dependent [U-14C]glucose incorporation into cellular lipids was also significantly reduced in C2 cell line suggesting an alteration in lipogenesis. In wild type LMH cells, SHC which is involved in Ras pathway, also served as a substrate for insulin receptor tyrosine kinase. In C2 cells, SHC expression, its association with the insulin receptor and its tyrosine phosphorylation were largely increased. Two forms of the regulatory subunit of PI 3-kinase were present: p85 and p55 forms. Furthermore, C2 cells displayed increased basal phosphatidylinositol (PI) 3'-kinase activity. This report demonstrates a role for cIRS-1 in the metabolic and mitogenic actions of insulin in LMH cells. However, the overexpression of cIRS-1 antisense did not completely abolish cell proliferation. This may be explained by the exacerbation of an alternative pathway that only partly compensate for the knocking out of cIRS-1 gene: the overexpression of SHC.
Mol Cell Endocrinol 1998 Feb
PMID:Insulin receptor substrate 1 antisense expression in an hepatoma cell line reduces cell proliferation and induces overexpression of the Src homology 2 domain and collagen protein (SHC). 960 20

Pulmonary sarcoidosis involves development of parenchymal granulomata that usually resolve spontaneously; however, it remains unclear what pathogenic mechanisms are responsible for the progression to local or diffuse fibrosis with irreversible lung remodeling that occurs in 20% of patients. Alveolar macrophages have a pivotal role in sarcoidosis, releasing mediators including insulin-like growth factor (IGF)-1, a potent profibrogenic molecule. IGF-1 bioavailability in the lung is dependent on at least six high-affinity IGF-binding proteins (IGFBP), which mainly inhibit IGF-1 action. We have investigated their presence in patients with established stage III sarcoidosis to determine whether IGF-1 and IGFBP contribute to the fibrogenic process in these patients and as such contribute to the (clinical) progression of the disease. The fibroblast mitogenic potential of bronchoalveolar lavage fluid (BALF) was more than 3-fold higher (P < 0.005) in sarcoid patients. Sarcoid BALF-induced activity could be inhibited (P < 0.0005) by neutralizing antibodies to IGF-1. We established the IGFBP profile of BALF with Western ligand analysis and quantified expression of IGFBP-3 by immunoblotting. IGFBP-2 and IGFBP-4 predominate in normal and sarcoid BALF, but IGFBP-3 occurs only as a modified, smaller, 29-kD form, expression of which was raised (P < 0.003) in sarcoid patients. Gene expression of IGF-1 and IGFBP-3 was demonstrated by reverse transcription-polymerase chain reaction in BAL cells. Thus, local production of pro-fibrogenic IGF-1 may be subject to substantial post-translational regulation by associated IGFBP and IGFBP proteases that may contribute to enhanced fibrogenesis in sarcoidosis patients with evidence of progression or (development) of fibrosis.
Am J Respir Cell Mol Biol 1998 Aug
PMID:Expression of insulin-like growth factor binding proteins in bronchoalveolar lavage fluid of patients with pulmonary sarcoidosis. 969 97


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