Multiple Signaling Pathways of the Insulin-Like Growth Factor 1 Receptor in Protection from Apoptosis

Peruzzi, Francesca; Prisco, Marco di; Dews, Michael; Salomoni, Paolo; Grassilli, Emanuela; Romano, Gaetano; Calabretta, Bruno; Baserga, Renato

doi:10.1128/mcb.19.10.7203

Cited by 456 publications

(462 citation statements)

References 80 publications

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“…In 32D cells, high levels of expression of the IGF-IR result in di erentiation and eventually cell death (Valentinis et al, 1999b). Ectopic expression of IRS-1 inhibits di erentiation and promotes rapid growth (Valentinis et al, 1999b;Peruzzi et al, 1999). Indeed, the present experiments con®rm that the combined e ect of the IGF-IR and IRS-1 is to increase the aggressiveness of cells, as demonstrated by colony formation in soft agar and tumor formation in nude mice.…”

Section: Effect Of Irs-1 On the Growth Of Lncap Cells In Nude Micesupporting

confidence: 57%

IGF-I receptor signaling in a prostatic cancer cell line with a PTEN mutation

et al. 2000

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LNCaP prostatic cancer cells are characterized by having a PTEN mutation, low levels of type 1 insulinlike growth factor receptor (IGF-IR) and no IRS-1, one of the major substrates of the IGF-IR. The absence of IRS-1, an activator of PI3-kinase, is compensated in these cells by the mutation in PTEN, an inhibitor of PI3-kinase. However, IGF-IR signaling in the absence of IRS-1 can cause cell di erentiation and growth arrest. We hypothesized that these three characteristics may not be unrelated, speci®cally that, together, they may favor the metastatic spread of prostatic cancer cells without decreasing their growth potential. In support of this hypothesis, we report here that: (1) IRS-1 expression increases cell adhesion and decreases cell motility; (2) over-expression of the IGF-IR, in the absence of IRS-1, causes growth arrest and (3) a combination of IGF-IR and IRS-1 restores the transformed phenotype of LNCaP cells. These ®ndings suggest a mechanism by which prostatic cancer cells can achieve metastatic potential without interfering with their growth potential.

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Section: Effect Of Irs-1 On the Growth Of Lncap Cells In Nude Micesupporting

confidence: 57%

IGF-I receptor signaling in a prostatic cancer cell line with a PTEN mutation

et al. 2000

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“…IGF1R signaling is a potent promoter of cell survival in a variety of cultured mammalian cells. [19][20][21] To test whether loss of IGF1R signaling leads to increased apoptosis in a developing vertebrate embryo, we measured the activity of caspase 3, an executioner caspase. Reducing IGF1R signaling resulted in a four-fold, highly significant increase in caspase 3 activities over controls and coinjection of the igf1r MOs along with igf1r mRNA reduced caspase 3 activities to the basal level (Figure 4a).…”

Section: Resultsmentioning

confidence: 99%

Insulin-like growth factor signaling regulates zebrafish embryonic growth and development by promoting cell survival and cell cycle progression

et al. 2007

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Although much is known about the global effects of insulin-like growth factor 1 receptor (IGF1R)-mediated signaling on fetal growth and the clinical manifestations resulting from IGF/IGF1R deficiencies, we have an incomplete understanding of the cellular actions of this essential pathway during vertebrate embryogenesis. In this study, we inhibited IGF1R signaling during zebrafish embryogenesis using antisense morpholino oligonucleotides or a dominant-negative IGF1R fusion protein. IGF1R inhibition resulted in reduced embryonic growth, arrested development and increased lethality. IGF1R-deficient embryos had significant defects in the retina, inner ear, motoneurons and heart. No patterning abnormalities, however, were found in the brain or other embryonic tissues. At the cellular level, IGF1R inhibition increased caspase 3 activity and induced neuronal apoptosis. Coinjection of antiapoptotic bcl2-like mRNA attenuated the elevated apoptosis and rescued the retinal and motoneuron defects, but not the developmental arrest. Subsequent cell cycle analysis indicated an increased percentage of cells in G1 and a decreased percentage in S phase in IGF1R-deficient embryos independent of apoptosis. These results provide novel insight into the cellular basis of IGF1R function and show that IGF1R signaling does not function as an anteriorizing signal but regulates embryonic growth and development by promoting cell survival and cell cycle progression.

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“…Unexpectedly, we found that daily addition of IGF2 increased apoptosis in beta cells and probably in their precursors in GK pancreatic rudiment, suggesting that the anti-apoptotic effect of IGF2 is deficient in embryonic GK pancreas. The main signalling pathway for the antiapoptotic effect of IGFs involves IGF1R, IRS1 and IRS2, phosphatidylinositol 3 kinase, AKT and Bclassociated death promoter (BAD) [43,44]. An anomaly in these antiapoptotic signalling pathways remains to be determined in embryonic GK pancreas.…”

Section: Discussionmentioning

confidence: 99%

Defective IGF2 and IGF1R protein production in embryonic pancreas precedes beta cell mass anomaly in the Goto–Kakizaki rat model of type 2 diabetes

et al. 2007

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Aims/hypothesis The Goto-Kakizaki (GK) rat is a spontaneous model of type 2 diabetes. Defective beta cell mass detectable in late fetal age precedes the onset of hyperglycaemia. Our hypothesis was that an embryonic IGF production deficiency might be involved in beta cell mass anomaly in the diabetic GK rat. To test this, we evaluated during pancreatic organogenesis: (1) the beta cell development in GK rats on embryonic day (E) 13.5 and E18.5; (2) IGF2 and IGF1 receptor (IGF1R) pancreatic protein production on E13.5 and E18.5; (3) the in vitro development of GK pancreatic rudiment on E13.5; and (4) the in vitro effect of IGF2 addition on beta cell mass. Materials and methods Beta cell quantitative analyses were determined by immunohistochemistry and morphometry. IGF2 and IGF1R pancreatic protein production was evaluated using western blot analyses. Dorsal pancreatic rudiments were dissected on E13.5, separated from surrounding mesenchyme and cultured for 7 days without or with recombinant IGF2. Results While beta cell mass was already decreased on E18.5, the differentiation of the first beta cells was in fact normal in E13.5 GK pancreas. Moreover, defective IGF2 and IGF1R protein production was detected in GK pancreatic rudiment as early as E13.5. The isolated GK pancreatic rudiment as maintained in vitro mimics the GK beta cell deficiency observed in vivo. This last approach enabled us to show that GK beta cells were fully responsive to IGF2 as far as their net growth is concerned. Conclusions/interpretation In diabetic GK rat, defective IGF2 and IGF1R protein production in embryonic pancreas precedes beta cell mass anomaly. IGF2 supplementation expands the pool of beta cells.

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Multiple Signaling Pathways of the Insulin-Like Growth Factor 1 Receptor in Protection from Apoptosis

Cited by 456 publications

References 80 publications

IGF-I receptor signaling in a prostatic cancer cell line with a PTEN mutation

IGF-I receptor signaling in a prostatic cancer cell line with a PTEN mutation

Insulin-like growth factor signaling regulates zebrafish embryonic growth and development by promoting cell survival and cell cycle progression

Defective IGF2 and IGF1R protein production in embryonic pancreas precedes beta cell mass anomaly in the Goto–Kakizaki rat model of type 2 diabetes

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