Insulin-like growth factor II stimulates cell proliferation through the insulin receptor

Morrione, Andrea; Valentinis, Barbara; Xu, Shi-Qiong; Yumet, Gladys; Louvi, Angeliki; Efstratiadis, Argiris; Baserga, Renato

doi:10.1073/pnas.94.8.3777

Cited by 208 publications

(153 citation statements)

References 43 publications

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“…More recently, it was reported that overexpression of IGF-II in ␤-cells in transgenic mice resulted in increased ␤-cell mass (17); it was proposed that more efficient IR activation by IGF-II could partly contribute to this effect. That IGF-II action through IR can indeed stimulate cell proliferation has been clearly demonstrated using a fibroblast cell line derived from IGF-1R-deficient mice (16). It is also conceivable that in the absence of insulin, the existence of empty IRs might result in an increased number of IR-IGF-1R hybrid receptors that can efficiently bind IGF-I.…”

Section: Resultsmentioning

confidence: 96%

“…However, hyperglycemia per se cannot be responsible for ␤-cell hyperplasia, since both insulin-and IR-deficient mice become hyperglycemic. An attractive hypothesis is that lack of insulin could favor IGF-II action through IR, which might stimulate cell proliferation to a greater extent than insulin itself (16). More recently, it was reported that overexpression of IGF-II in ␤-cells in transgenic mice resulted in increased ␤-cell mass (17); it was proposed that more efficient IR activation by IGF-II could partly contribute to this effect.…”

Section: Resultsmentioning

confidence: 99%

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Endocrine pancreas in insulin receptor-deficient mouse pups.

et al. 2001

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Insulin receptor (IR)-deficient pups rapidly become hyperglycemic and hyperinsulinemic and die of diabetic ketoacidosis within a few days. Immunocytochemical analysis of the endocrine pancreas revealed that IR deficiency did not alter islet morphology or the number of ␤-, ␣-, ␦-, and pancreatic polypeptide (PP) cells. The lack of IR did not result in major changes in the expression of islet hormone genes or of ␤-cell-specific marker genes encoding pancreas duodenum homeobox-containing transcription factor-1 (PDX-1), glucokinase (GCK), and GLUT2, as shown by reverse transcriptase-polymerase chain reaction analysis. The serum glucagon levels in IR-deficient and nondiabetic littermates were comparable. Finally, total insulin content in the pancreas of IR-deficient pups was gradually depleted, indicating sustained insulin secretion, not compensated for by increased insulin biosynthesis. These findings are discussed in light of recent results suggesting a role of IR in ␤-cell function. Diabetes 50 (Suppl. 1):S146-S149, 2001 S everal studies using transgenic and knockout mice have established that the development and function of pancreatic ␤-cells are controlled by a number of genes encoding specific transcription factors such as pancreas duodenum homeobox-containing transcription factor-1 (PDX-1), hormones, growth factors such as IGF-I and IGF-II and their receptors, or proteins involved in glucose sensing such as glucokinase (GCK) and the glucose transporter GLUT2 (1,2).The biological effects of insulin are mediated by the insulin receptor (IR), a heterotetrameric (␣ 2 ␤ 2 ) membrane tyrosine kinase. After insulin binding, the activated IR phosphorylates docking proteins such as insulin receptor substrate (IRS)-1 or IRS-2. These adaptor proteins subsequently recruit intracellular mediators, which in turn lead to the activation of various signaling pathways (3). Although muscle, liver, and fat tissue represent the major target tissues for the metabolic action of insulin, IR is thought to be present in most cells and its expression in the ␤-cell has also been documented (4). Despite a number of in vivo studies of humans or animal models, the question as to whether IR expression in ␤-cells has any functional significance has remained a matter of debate for several years. It has emerged from some recent work using purified ␤-cells or ␤-cell lines that insulin action through IR might play an important autocrine role in normal ␤-cell function. This conclusion is based on the observations that insulin can stimulate insulin gene transcription as well as insulin secretion in ␤-cells (5-7). It was further shown that the signaling pathways activated by IR that lead to the transcriptional upregulation of the insulin gene involve the IRS-2/phosphatidylinositol 3-kinase/p70 S6 kinase and the calcium/calmodulindependent protein (CaM) kinase cascades (5).We and others have previously reported that targeted disruption of the IR gene (Insr) in the mouse resulted in diabetic ketoacidosis and neonatal lethality (8,9). IR deficiency did...

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Endocrine pancreas in insulin receptor-deficient mouse pups.

et al. 2001

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“…Evidence derived from targeted mutagenesis of the two mouse insulin genes suggests that insulin plays a small role in mouse embryonic growth [9]. Interestingly, activation of IRs in response to IGF-2 seems to have a broader range of effects to stimulate embryonic growth than insulin binding to IRs [8,22]. In humans, fetal insulin acts primarily at the level of the adipocyte to stimulate growth.…”

Section: Discussionmentioning

confidence: 99%

Lack of insulin receptors affects the formation of white adipose tissue in mice. A morphometric and ultrastructural analysis

et al. 1998

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Insulin receptors (IRs) mediate insulin action upon target cells [1]. Disorders of IR function are a well established, albeit rare, cause of insulin resistance and diabetes mellitus [2±4]. In mice, targeted ablation of IR expression results in lethal diabetic ketoacidosis [5±7]. Unlike children with homozygous nonsense mutations of the IR gene, IR ±/± mice do not develop substantial growth retardation, fasting hypoglycaemia, or signs of hyperandrogenism.The lack of gross growth retardation in IR ±/± mice is an unexpected finding. To understand better the causes of this apparent discrepancy between the human paradigm and the mouse model, we have recently performed genetic crosses of IR ±/± mice with mice lacking insulin-like growth factor-1 (IGF-1) receptors (IGF-1Rs) and . The results of these experiments indicate that IRs do indeed affect embryonic growth. The growth-promoting actions of IRs occur in response to IGF-2, rather than insulin, binding. The interaction between IRs and IGF-2 plays an important role during the last phase of mouse gestation. Based on these data, we have suggested that the lack of a growth-retarded phenotype in IR ±/± mice may be due to the shorter duration of mouse gestation Diabetologia (1998) 41: 171±177

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“…The ability of IGF-II R to recruit signal transduction proteins is not well documented in the literature. 15 To learn more about the role of the insulin growth factor family in regulating human erythropoiesis, we employed a well-defined serum-free cloning system to examine the direct effect of INS and IGF-I on survival and cloning efficiency of the CD34 + cells. We also studied the development of BFU-E colonies compared to the effect of other cytokines and growth factors which have been reported to enhance erythropoiesis.…”

Section: Introductionmentioning

confidence: 99%

The role of insulin (INS) and insulin-like growth factor-I (IGF-I) in regulating human erythropoiesis. Studies in vitro under serum-free conditions – comparison to other cytokines and growth factors

et al. 1998

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The role of insulin (INS), and insulin-like growth factor-I (IGF-I Both INS and IGF-I activated signal transduction in maturing human erythropoietic cells as determined by phosphorylation of the insulin receptor substrate-2 (IRS-2) protein. We also found by RT-PCR that mRNA coding for INS-R is expressed in FACS sorted CD34؉ , c-kit-R ؉ marrow cells, and in cells isolated from BFU-E and CFU-GM colonies. Expression of INS-R protein on these cells was subsequently confirmed by cytofluorometry. In contrast, the receptor for insulin-like growth factor-I (IGF-IR) was not detected on CD34؉ cells, and was first easily detectable on more differentiated cells derived from day 6 BFU-E and CFU-GM colonies. We conclude that INS and IGF-I may be survival factors for human CD34 ؉ cells, but are not required during early erythropoiesis. In contrast, both growth factors may play some role at the final stages of erythroid maturation.

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Insulin-like growth factor II stimulates cell proliferation through the insulin receptor

Cited by 208 publications

References 43 publications

Endocrine pancreas in insulin receptor-deficient mouse pups.

Endocrine pancreas in insulin receptor-deficient mouse pups.

Lack of insulin receptors affects the formation of white adipose tissue in mice. A morphometric and ultrastructural analysis

The role of insulin (INS) and insulin-like growth factor-I (IGF-I) in regulating human erythropoiesis. Studies in vitro under serum-free conditions – comparison to other cytokines and growth factors

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