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

The type 1 insulin-like growth factor receptor (IGF-1R), a transmembrane tyrosine kinase, is widely expressed across many cell types in foetal and postnatal tissues. Activation of the receptor following binding of the secreted growth factor ligands IGF-1 and IGF-2 elicits a repertoire of cellular responses including proliferation, and the protection of cells from programmed cell death or apoptosis. As a result, signalling through the IGF-1R is the principal pathway responsible for somatic growth in foetal mammals, whereas somatic growth in postnatal animals is achieved through the synergistic interaction of growth hormone and the IGFs. Forced overexpression of the IGF-1R results in the malignant transformation of cultured cells: conversely, downregulation of IGF-1R levels can reverse the transformed phenotype of tumour cells, and may render them sensitive to apoptosis in vivo. Elevated levels of IGF-IR are observed in a variety of human tumour types, whereas epidemiological studies implicate the IGF-1 axis as a predisposing factor in the pathogenesis of human breast and prostate cancer. The IGF-1R has thus emerged as a therapeutic target for the development of antitumour agents. Recent progress towards the elucidation of the three-dimensional structure of the extracellular domain of the IGF-1R represents an opportunity for the rational assembly of small molecule antagonists of receptor function for clinical use.
Cell Mol Life Sci 2000 Jul
PMID:Structure and function of the type 1 insulin-like growth factor receptor. 1096 44

Within the class of insulin and insulin-like growth factor receptors, detailed information about the molecular recognition event at the hormone-receptor interface is limited by the absence of suitable co-crystals. We describe the use of a biologically active insulin derivative labeled with the NBD fluorophore (B29NBD-insulin) to characterize the mechanism of reversible 1:1 complex formation with a fragment of the insulin receptor ectodomain. The accompanying 40 % increase in the fluorescence quantum yield of the label provides the basis for a dynamic study of the hormone-receptor binding event. Stopped-flow fluorescence experiments show that the kinetics of complex formation are biphasic comprising a bimolecular binding event followed by a conformational change. Displacement with excess unlabeled insulin gave monophasic kinetics of dissociation. The rate data are rationalized in terms of available experiments on mutant receptors and the X-ray structure of a non-binding fragment of the receptor of the homologous insulin-like growth factor (IGF-1).
J Mol Biol 2000 Oct 20
PMID:Ligand-induced conformational change in the minimized insulin receptor. 1102 83

Increased concentrations of TGF-beta 1 in endometriotic tissue are considered important in the pathophysiology of endometrial diseases since TGF-beta 1 may inhibit natural killer activity and induce angiogenesis and proliferation of endometrial stromal cells. In the present study we report on TGF-beta 1, IGF-1 and their receptor localization, as detected by Northern hybridization and immunohistochemistry, in ovarian endometriotic tissues removed during surgical procedures. We detected comparable expression of IGF-1 and IGF-1 receptor in the stromal and epithelial compartments, thus confirming disregulated expression of the IGF system in ovarian endometriosis. On the contrary, strongly increased TGF-beta 1 steady state level mRNA expression was detected in all endometriotic samples. In addition, we demonstrated weak TGF-beta 1 immunohistochemical expression in the epithelial lining and intense expression in the cellular stroma of ovarian endometriomas, thus suggesting that TGF-beta 1 could have an important role in the maintenance and propagation of the disease. On the basis of these preliminary results we can assume that TGF-beta 1, IGF-1 and their receptors may play an important role in the pathogenesis of endometriosis.
Int J Mol Med 2001 Apr
PMID:Transforming growth factor-beta 1 and insulin-like growth factor-1 expression in ovarian endometriotic cysts: a preliminary study. 1125 86

Serum levels of growth hormone (GH) can vary. Low levels of GH can result in a dwarf phenotype and have been positively correlated with an increased life expectancy. High levels of GH can lead to gigantism or a clinical syndrome termed acromegaly and has been implicated in diabetic eye and kidney damage. Additionally the GH/IGF-1 system has been postulated as a risk factor for several types of cancers. Thus both elevated and suppressed circulating levels of GH can have pronounced physiological effects. More than a decade ago the first drug of a new class, a GH antagonist, was discovered. This molecule is now being tested for its ability to combat the effects of high circulating levels of GH. Here, we discuss some of the detrimental actions of GH, and how a GH antagonist can be used to combat these effects.
Trends Mol Med 2001 Mar
PMID:Biological effects of growth hormone and its antagonist. 1128 84

Interactions between thymocytes and thymic stromal cells are essential for thymocyte differentiation, but little evidence has been presented to directly show in vivo functions or interactions of the stromal cells. Among the stromal cells, the thymic epithelial cell has been considered to have profound effect on thymocyte differentiation and maturation. The calcium-depleted medium, originally developed for the culture of mouse epidermal cells, was applied for the culture of the mouse thymic epithelial cells, and successfully, an epithelial cell line, IT-76MHC was obtained from the mouse thymus. IT-76MHC cells were identified as distinct mouse thymic epithelial cells by 1/ mosaic-like arrangement, 2/ presence of well-developed desmosome and 3/ tonofilaments, 4/ positivity for cytokeratin, and 5/ induced expression of MHC class I and II by IFN-gamma treatment. IGF-1, IGF-2, oxytocin and vasopressin were also detected immunohistochemically in IT-76MHC cells. Furthermore, the IT-76MHC thymic epithelial cells, when injected intrathymically in the allogeneic mouse, prolonged the survival of skin graft from the same donor strain that IT-76MHC cells were derived. These results demonstrate that the thymic epithelial cell line IT-76MHC produces modest thymocyte survival factors as well as a growth suppressor, and that IT-76MHC cells have the ability to induce transplantation tolerance probably through their expression of MHC class I and II molecules. Taken altogether, the IT-76MHC thymic epithelial cells have been proved to be useful tools to better understand the in vivo functions of thymic epithelial cells, and to gain a deep insight into their involvement in the critical selection process of thymocytes which still remains obscure. Finally and additionally, literatures so far reported on thymic epithelial cells in culture, especially lines and clones, are reviewed and their identity as well as their functions are discussed.
Cell Mol Biol (Noisy-le-grand) 2001 Feb
PMID:Establishment of a mouse thymic epithelial cell line, IT-76MHC and a brief review on cultured thymic epithelial cells. 1129 44

The thymus is a primary lymphoid organ with both endocrine and immune functions. There is a large body of evidence indicating the existence of a complex neuroendocrine control of the thymus physiology. This is supported by the historic observation that the thymus becomes involuted during the response to stress. The thymus is dramatically affected by the acute phase response (APR), a systemic reaction to tissue injury and/or infection accompanied by profound neuroendocrine and metabolic changes. The APR comprises alterations in behavior, body temperature, and production and release of cytokines, particularly interleukin (IL)-1, IL-6 and TNFalpha, and glucocorticoids (GCs) and is characterized by suddenly increased production of so-called acute phase proteins (APPs). The stimulation of APR activates the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the suppression of specific immunity, which might serve to protect the organism from adverse immune reactions; the immunostimulatory hormones (e.g., PRL, GH, IGF-1) are suppressed, whereas the production of APPs in the liver is stimulated by IL-6, catecholamines and GCs. The most striking effect of the latter on the immune system is the induction of apoptosis in the thymus. In concert with GCs, elevated levels of catecholamines also selectively suppress immune response mechanisms. APR may be regarded as an emergency response that represents a switch of the host defense from the adaptive immune response which is slow to develop and is commanded by the thymus and T-lymphocytes to a less specific, but more rapid and intense reaction. Here we discuss the immunoregulatory changes during the APR with a special emphasis on the role of thymus in this process.
Cell Mol Biol (Noisy-le-grand) 2001 Feb
PMID:The thymus and the acute phase response. 1129 49

Leptin was originally believed to be an exclusively adipocyte-derived hormone regulating appetite and energy balance. It has recently become apparent that leptin is actively expressed in a number of other tissues including the CNS and pituitary, as well as brain- and pituitary-derived cell lines. However, the factors controlling leptin expression in cells of neuroectodermal origin are unknown. The mouse leptin gene 5'-flanking DNA contains multiple AP-1 and SRF-1 binding sites as well as a consensus CRE site at -491 to -482 bp. In addition, a number of potential PIT1 and Oct-1 binding sites may contribute to leptin gene transcription in pituitary and brain. We have used leptin promoter-luciferase reporter constructs to examine the regulation of the leptin promoter in 3T3-L1 preadipocytes, C6 glioma cells, and GH3 pituitary cells in response to serum and hormonal stimuli. Cells were transiently transfected with reporter constructs containing either the proximal 500 bp of the leptin promoter (-500-luc) or 6000 bp of the leptin gene 5' flanking region (-6000-luc). Functional analysis indicates that the leptin promoter is constitutively active in all 3 cell lines. Transcriptional activity was significantly higher with a -500 to +9 promoter than with a construct containing -6000 to +9 bp of 5' flanking DNA, indicating the presence of repressor elements which may contribute to the tissue-specific regulation of leptin expression. However, qualitatively similar results were observed with both constructs in response to serum and hormonal manipulation. Leptin promoter activity was significantly stimulated by serum in all cell lines, although to varying extents. In contrast, the response of the leptin promoter to insulin, IGF-1 and dibutyryl cAMP was cell-type specific and dependent on the presence or absence of FBS in the culture medium. Insulin, IGF-1 and dibutyryl cAMP each caused an approximately two-fold stimulation of leptin promoter activity in 3T3-L1 cells under serum-free conditions, but had no significant effect in the presence of 10% FBS. In contrast, dibutyryl cAMP markedly stimulated leptin promoter activity (5-8-fold) in C6 or GH3 cells in the presence or absence of FBS, whereas insulin or IGF-1 had minimal effects. These findings support our previous studies on the regulation of leptin steady state mRNA levels in C6 cells and demonstrate tissue-specific differences in the regulation of leptin gene transcription in adipose vs. neuroectodermal tissues.
Mol Cell Endocrinol 2001 May 15
PMID:Transcriptional regulation of the leptin gene promoter in rat GH3 pituitary and C6 glioma cells. 1136 43

In MCF-7 breast cancer cells, the insulin-like growth factor 1 receptor (IGF-1R) and the oestrogen receptor (ER) are coexpressed and the two signalling systems are engaged in a crosstalk that results in synergistic growth. However, coupling between the signalling cascades is poorly understood. Oestradiol enhances IGF-1R signalling by inducing the expression of insulin receptor substrate 1 (IRS-1), a substrate of the IGF-1R. Oestradiol induced expression of IRS-1 results in enhanced tyrosine phosphorylation of IRS-1 after IGF-1 stimulation, followed by enhanced mitogen activated protein kinase, phosphoinositide 3' kinase, and Akt activation. Oestradiol can also potentiate the effect of IGF-1 on the expression of cyclin D1 and cyclin E, and on the phosphorylation of the retinoblastoma protein (RB). These effects are greatly diminished in SX13 cells, which exhibit a 50% reduction in IGF-1R expression but few functional IGF-1Rs at the surface. Oestradiol and IGF-1 regulate the expression of two cyclin dependent kinase inhibitors, p21 and p27, differently. Whereas IGF-1 increases p21 expression and reduces p27 expression, oestradiol has no effect on p21. In summary, in MCF-7 cells, oestrogen potentiates the effect of IGF-1 on IGF-1R signalling and its effects on certain cell cycle components.
Mol Pathol 2001 Jun
PMID:Insulin-like growth factor 1 and oestradiol promote cell proliferation of MCF-7 breast cancer cells: new insights into their synergistic effects. 1137 26

The 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase (3beta-HSD) isoenzymes catalyze an essential step in the formation of all classes of active steroid hormones. We have recently shown that 3beta-HSD type 1 gene expression is specifically induced by interleukin (IL)-4 and IL-13 in several human cancer cell lines and in normal human mammary and prostatic epithelial cells in primary culture. There is evidence that IL-4 stimulates bifurcating signaling pathways in which the Stat6-signal pathway is involved in differentiation and gene regulation, whereas insulin receptor substrate (IRS) proteins mediate the mitogenic action of IL-4. As a matter of fact, we have shown that IL-4-activated Stat6 in all cell lines studied, where IL-4 induced 3beta-HSD type 1 expression but not in those cell lines that failed to respond to IL-4. The mechanism of the induction of 3beta-HSD type 1 gene expression was further characterized in ZR-75-1 human breast cancer cells. We have also found that IL-4 rapidly induced IRS-1 and IRS-2 phosphorylation in these cell lines. Moreover, insulin-like growth factor (IGF)-1 and insulin, which are well known to cause IRS-1 and IRS-2 phosphorylation, increased the stimulatory effect of IL-4 on 3beta-HSD activity. IRS-1 and IRS-2 are adapter molecules that provide docking sites for different SH2 domain-containing proteins, leading to the activation of multiple pathways, such as the phosphatidylinositol (PI) 3-kinase and the mitogen-activated protein (MAP) pathways. The inhibition of IL-4-induced 3beta-HSD expression by PI 3-kinase inhibitors (wortmannin and LY294002) as well as an inhibitor of MAP kinase activation (PD98059), indicates the involvement of those pathways in this response to IL-4. Wortmannin also blocked MAP kinase activation by IL-4, insulin and IGF-1 suggesting that the MAP kinase cascade acts as a downstream effector of PI 3-kinases. Furthermore, we showed that the PKC activator phorbol-12-myristate-13-acetate (PMA) also potentiated the IL-4-induced 3beta-HSD activity, thus suggesting that one signaling molecule that is involved in the signal transduction of the IL-4 action on 3beta-HSD type 1 expression is also a substrate for PKC. Taken together, these findings suggest the existence of a novel mechanism of gene regulation by IL-4. This mechanism would involve in the phosphorylation of IRS-1 and IRS-2, which transduce the IL-4 signal through a PI 3-kinase- and MAP kinase-dependent signaling pathway. However, the inability of IGF-1, insulin and PMA to stimulate 3beta-HSD type 1 expression by themselves in the absence of IL-4 indicates that the multiple pathways downstream of IRS-1 and IRS-2 must act in cooperation with an IL-4-specific signaling molecule, such as the transcription factor Stat6. It is also of interest to note that there also appear to be differences between the regulation of the 3beta-HSD type 1 and type 2 promoters.
J Steroid Biochem Mol Biol
PMID:Multiple signal transduction pathways mediate interleukin-4-induced 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase in normal and tumoral target tissues. 1138 80

Receptors of the insulin/insulinlike growth factor (IGF) family have been implicated in the regulation of pancreatic beta-cell growth and insulin secretion. The insulin receptor-related receptor (IRR) is an orphan receptor of the insulin receptor gene (Ir) subfamily. It is expressed at considerably higher levels in beta cells than either insulin or IGF-1 receptors, and it has been shown to engage in heterodimer formation with insulin or IGF-1 receptors. To address whether IRR plays a physiologic role in beta-cell development and regulation of insulin secretion, we have characterized mice lacking IRR and generated a combined knockout of Ir and Irr. We report that islet morphology, beta-cell mass, and secretory function are not affected in IRR-deficient mice. Moreover, lack of IRR does not impair compensatory beta-cell hyperplasia in insulin-resistant Ir(+/-) mice, nor does it affect beta-cell development and function in Ir(-/-) mice. We conclude that glucose-stimulated insulin secretion and embryonic beta-cell development occur normally in mice lacking Irr.
Mol Cell Biol 2001 Aug
PMID:Preserved pancreatic beta-cell development and function in mice lacking the insulin receptor-related receptor. 1146 43


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