Mutation of the RGD sequence does not affect plasma membrane association and growth inhibitory effects of elevated IGFBP‐2 in vivo

Hoeflich, Andreas; Reisinger, Raquel; Vargas, Gustavo A.; Elmlinger, Martin W.; Schuett, Burkhardt S.; Jehle, Peter; Renner‐Müller, Ingrid; Lahm, Harald; Russo, Vincenzo; Wolf, Eckhard

doi:10.1016/s0014-5793(02)02935-6

Cited by 33 publications

(26 citation statements)

References 34 publications

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“…These findings are consistent with previous results (Hoeflich et al ., 1999, 2002) and support the hypothesis that the RGD‐motif is not required for the negative effects of IGFBP‐2 on somatic growth. We have shown previously that IGFBP‐2 also is a potent inhibitor of bone mass and bone lengths (Eckstein et al ., 2002) thus somatic growth inhibition is found both for body mass and skeletal parameters.…”

Section: Discussionsupporting

confidence: 75%

“…Studies III and IV were performed under semi‐barrier conditions in the mouse facility of the Leibniz Institute of Farm Animal Biology (FBN) in Dummerstorf, Germany. In both studies, transgenic C57BL/6 mice overexpressing either wild‐type IGFBP‐2 containing the intact RGD‐sequence (D‐mice; study III) or mutant IGFBP‐2 (E‐mice; study IV) lacking the RGD‐sequence motif (Hoeflich et al ., 2002) were used. If senescent mice were suffering from severe illness or had any other signs of distress, they were euthanized.…”

Section: Methodsmentioning

confidence: 99%

“…Owing to mutations of the GHR in Laron dwarfs and corresponding mouse mutants being associated with a drastic reduction of growth, it was investigated whether moderate growth impairment, for example, caused by overabundance of IGF1 inhibitory binding proteins (Hoeflich et al ., 2004), may still have significant consequences for life expectancy and sexual development. Consequently, two different IGFBP‐2 transgenic mouse models (Hoeflich et al ., 1999, 2002) overexpressing either wild‐type mouse IGFBP‐2 (D‐mice) or mutated IGFBP‐2 lacking the RGD‐motif required for integrin binding (Pereira et al ., 2004) and carrying an RGE‐sequence instead (E‐mice) were investigated. Circulating IGF1 levels and IGFBP‐2 transgene expression levels in different tissues and compartments were similar in both transgenic lines, and this was due to the fact that identical expression vectors were used for generation of both mouse models (Hoeflich et al ., 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, two different IGFBP‐2 transgenic mouse models (Hoeflich et al ., 1999, 2002) overexpressing either wild‐type mouse IGFBP‐2 (D‐mice) or mutated IGFBP‐2 lacking the RGD‐motif required for integrin binding (Pereira et al ., 2004) and carrying an RGE‐sequence instead (E‐mice) were investigated. Circulating IGF1 levels and IGFBP‐2 transgene expression levels in different tissues and compartments were similar in both transgenic lines, and this was due to the fact that identical expression vectors were used for generation of both mouse models (Hoeflich et al ., 2002). The oncogenic potential of IGFBP‐2 for glioma progression is mediated by the RGD‐motif, integrin β1, and integrin‐linked kinase and results in the activation of the NF‐κB network (Holmes et al ., 2012).…”

Section: Introductionmentioning

confidence: 99%

“…In fact, by direct comparison of D‐ and E‐mice, we were able to demonstrate that the RGD‐motif present in IGFBP‐2 is involved in the regulation of GLUT4 trafficking and glucose clearance after oral glucose administration (Reyer et al ., 2015). The RGD‐motif is distinct from the two IGF‐binding sites and both variants of IGFBP‐2 bind IGF2 with high affinity as demonstrated by Western ligand blotting (Hoeflich et al ., 1999, 2002). Here, our experimental system was used for testing other pleiotropic functions of wild‐type vs. mutant IGFBP‐2 overabundance on somatic growth, time of sexual maturity, and lifespan.…”

Section: Introductionmentioning

confidence: 99%

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Dissociation of somatic growth, time of sexual maturity, and life expectancy by overexpression of an RGD ‐deficient IGFBP ‐2 variant in female transgenic mice

et al. 2015

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SummaryImpaired growth is often associated with an extension of lifespan. However, the negative correlation between somatic growth and life expectancy is only true within, but not between, species. This can be observed because smaller species have, as a rule, a shorter lifespan than larger species. In insects and worms, reduced reproductive development and increased fat storage are associated with prolonged lifespan. However, in mammals the relationship between the dynamics of reproductive development, fat metabolism, growth rate, and lifespan are less clear. To address this point, female transgenic mice that were overexpressing similar levels of either intact (D‐mice) or mutant insulin‐like growth factor‐binding protein‐2 (IGFBP‐2) lacking the Arg‐Gly‐Asp (RGD) motif (E‐ mice) were investigated. Both lines of transgenic mice exhibited a similar degree of growth impairment (−9% and −10%) in comparison with wild‐type controls (C‐mice). While in D‐mice, sexual maturation was found to be delayed and life expectancy was significantly increased in comparison with C‐mice, these parameters were unaltered in E‐mice in spite of their reduced growth rate. These observations indicate that the RGD‐domain has a major influence on the pleiotropic effects of IGFBP‐2 and suggest that somatic growth and time of sexual maturity or somatic growth and life expectancy are less closely related than thought previously.

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Section: Discussionsupporting

confidence: 75%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dissociation of somatic growth, time of sexual maturity, and life expectancy by overexpression of an RGD ‐deficient IGFBP ‐2 variant in female transgenic mice

et al. 2015

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Fibroblast growth factor‐2 over‐rides insulin‐like growth factor‐I induced proliferation and cell survival in human neuroblastoma cells

Russo

Andaloro

Fornaro

et al. 2003

Journal Cellular Physiology

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The insulin-like growth factor (IGF) system is a key regulator of cell growth, survival and differentiation, and these functions are co-modulated by other growth factors including fibroblast growth factor-2 (FGF-2). To investigate IGF/FGF interactions in neuronal cells, we employed neuroblastoma cells (SK-N-MC). In serum free conditions proliferation of the SK-N-MC cells was promoted by IGF-I (25 ng/ml), but blunted by FGF-2 (50 ng/ml). IGF-I-induced proliferation was abolished in the presence of FGF-2 even when IGF-I was used at 100 ng/ml. In addition to our previously described FGF-2 induced proteolytic cleavage of IGFBP-2, we found that FGF-2 increased IGFBP-6 levels in conditioned medium (CM) without affecting IGFBP-6 mRNA abundance. Modulation of IGFBP-2 and -6 levels were not significant mechanisms involved in the blockade of IGF-I action since the potent IGF-I analogues [QAYL]IGF-I and des(1-3)IGF-I (minimal IGFBP affinity) were unable to overcome FGF-2 inhibition of cell proliferation. FGF-2 treated cells showed morphological differentiation expressing the TUJ1 neuronal marker while cells treated with IGF-I alone showed no morphological change. When IGF-I was combined with FGF-2, however, cell morphology was indistinguishable from that seen with FGF-2 alone. FGF-2 inhibited proliferation and enhanced differentiation was also associated with a 70% increase in cell death. Although IGF-I alone was potently anti-apoptotic (60% decreased), IGF-I was unable to prevent apoptosis when administrated in combination with FGF-2. Gene-array analysis confirmed FGF-2 activation of the intrinsic and extrinsic apoptotic pathways and blockade of IGF anti-apoptotic signaling. FGF-2, directly and indirectly, overcomes the proliferative and anti-apoptotic activity of IGF-I by complex mechanisms, including enhancement of differentiation and apoptotic pathways, and inhibition of IGF-I induced anti-apoptotic signalling. Modulation of IGF binding protein abundance by FGF-2 does not play a significant role in inhibition of IGF-I induced mitogenesis.

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Insulin-like Growth Factor Binding Proteins in Development

Silha

Murphy

Advances in Experimental Medicine and Biology

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IGFBPs regulate growth and development by regulating IGF transport to tissues and IGF bioavailability to IGF receptors at cell membrane level. IGFBP excess leads predominantly to inhibition of IGF action and growth retardation with impaired organogenesis. Absence of human and also mouse ALS leads to decreased IGF-I levels in circulation and causes mild growth retardation. Although IGFBP KO mice demonstrate relatively minor phenotypes, the possibility of compensatory mechanisms that mask the phenotypic manifestation of lack of individual binding proteins needs to be further investigated. Recent studies of hepatic regeneration in IGFBP-1 KO mice and also with mutant IGFBP-3 Tg mice provide some limited support for the existence of IGF-independent mechanism of action in vivo.

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Mutation of the RGD sequence does not affect plasma membrane association and growth inhibitory effects of elevated IGFBP‐2 in vivo

Cited by 33 publications

References 34 publications

Dissociation of somatic growth, time of sexual maturity, and life expectancy by overexpression of an RGD ‐deficient IGFBP ‐2 variant in female transgenic mice

Dissociation of somatic growth, time of sexual maturity, and life expectancy by overexpression of an RGD ‐deficient IGFBP ‐2 variant in female transgenic mice

Fibroblast growth factor‐2 over‐rides insulin‐like growth factor‐I induced proliferation and cell survival in human neuroblastoma cells

Insulin-like Growth Factor Binding Proteins in Development

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