Insulin Receptor Substrate-1, p70S6K, and Cell Size in Transformation and Differentiation of Hemopoietic Cells

Valentinis, Barbara; Navarro, Magali; Zanocco-Marani, Tommaso; Edmonds, Pamela; McCormick, Jason; Morrione, Andrea; Sacchi, Ada; Romano, Gaetano; Reiss, Krzysztof; Baserga, Renato

doi:10.1074/jbc.m002271200

Cited by 94 publications

(179 citation statements)

References 53 publications

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“…Although this approach can successfully identify signalling pathways initiated by IRS proteins (Wang et al, 1993;Sun et al, 1997;Valentinis et al, 2000), our data show it may be difficult to discern the biology regulated by these activated pathways using cells that never expressed these proteins. Insulin-like growth factor-I treatment did not stimulate MAPK signalling in T47D-YA/IRS-2 cells, suggesting that IGF-IR stimulation of cell motility does not require stimulation of MAPK signalling.…”

Section: Discussionmentioning

confidence: 92%

Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells

et al. 2006

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Activation of the type I insulin-like growth factor receptor (IGF-IR) regulates several aspects of the malignant phenotype, including cancer cell proliferation and metastasis. Phosphorylation of adaptor proteins downstream of IGF-IR may couple IGF action to specific cancer phenotypes. In this study, we sought to determine if insulin receptor substrate-1 and -2 (IRS-1 and -2) mediate distinct biological effects in breast cancer cells. Insulin receptor substrate-1 and IRS-2 were expressed in T47D-YA breast cancer cells, which lack IRS-1 and -2 expression, yet retain functional IGF-IR. In the absence of IRS-1 and -2 expression, IGF-IR activation was unable to stimulate proliferation or motility in T47D-YA cells. Expression of IRS-1 resulted in IGF-I-stimulated proliferation, but did not affect motility. In contrast, expression of IRS-2 enhanced IGF-I-stimulated motility, but did not stimulate proliferation. The aIR-3, an inhibitor of the IGF-IR, was unable to affect these IGF-stimulated phenotypes unless IRS-1 or -2 was expressed. Thus, IGF-IR alone is unable to regulate important breast cancer cell phenotypes. In these cells, IRS proteins are required for and mediate distinct aspects of IGF-IRstimulated behaviour. As multiple agents targeting the IGF-IR are currently in early clinical trials, IRS expression should be considered as a potential biomarker for IGF-IR responsiveness.

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Section: Discussionmentioning

confidence: 92%

Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells

et al. 2006

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“…There are two forms of IRS-1 in Figure 6, depending on the plasmid used. In 32D-GR15-GR103 cells (lanes 6 and 7), the IRS-1 plasmid had the entire 3Ј untranslated region 26 that gives several bands, including a strong band (A, arrow) of the same size (about 7 kb) as the IRS-1 mRNA of p6 cells, which is the endogenous mouse IRS-1 (lane 1). In 32D-GR15-GR185 cells, the IRS-1 used had a deleted 3Ј untranslated region, giving a smaller sized RNA (arrow B, about 4 kb).…”

Section: Conditional Expression Of Irs-1 Mrnamentioning

confidence: 99%

“…The cDNA of the mouse insulin receptor substrate 1 (IRS-1) 26 was inserted into the HindIII restriction site of the SIN MSCV.pac containing either the HSP70 (pGR219) or the human CMV (pGR157) promoters. The IRS-1 cDNA under the control of the human CMV promoter contains the full-length messenger RNA, which includes 700 base pairs of untranslated region downstream of the stop codon.…”

Section: Plasmidsmentioning

confidence: 99%

Efficient in vitro and in vivo gene regulation of a retrovirally delivered pro-apoptotic factor under the control of the Drosophila HSP70 promoter

Romano

Reiss

et al. 2001

Gene Ther

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We have developed a self-inactivating retroviral vector system with an internal, inducible Drosophila HSP70 promoter. This vector system delivers the desired transgene into cells rapidly and efficiently. It generates mixed populations of transduced cells where the transgene is inducible, and does not require the isolation of specific clones. Since the transgene is not expressed (or poorly expressed) at the restrictive

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“…When IRS-1 levels are decreased by experimental procedures, cancer cells lose their transformed phenotype (D'Ambrosio et al, 1995;del Rincon et al, 2004). Over-expression or ectopic expression of IRS-1 causes cell transformation, including the ability to form colonies in soft agar and tumors in mice (Cristofanelli et al, 2000;Valentinis et al, 2000;DeAngelis et al, 2006;Dearth et al, 2006). IRS-1 is often over-expressed in human cancer (Chang et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Nuclear insulin receptor substrate-1 activates promoters of cell cycle progression genes

Chen

Baserga

2007

Oncogene

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The insulin receptor substrate-1 (IRS-1) is a docking protein of the insulin-like growth factor-1 (IGF-1) receptor and of the insulin receptor. IRS-1 sends a strong mitogenic, anti-apoptotic signal and plays an important role in cell transformation and cancer. IRS-1 translocates to nuclei of cells, where it increases the activity of the rDNA, c-myc and cyclin D1 promoters. We show, by chromatin immunoprecipitation, occupancy by IRS-1 of the same promoters. Both promoter activation and promoter occupancy are IGF-1-dependent. In cells that respond to IGF-1 but in which IRS-1 does not translocate to nuclei, promoter occupancy is absent and promoter activation is absent or much reduced. Transcriptional activation of c-myc and cyclin D1 promoters by nuclear IRS-1 does not occur with a mutant, inactive IRS-1 protein (deletion of the phosphotyrosine-binding domain, PTB) and does not require PI3-kinase activity. Taken together, these results indicate a novel mechanism by which nuclear IRS-1 activates cell cycle genes.

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Insulin Receptor Substrate-1, p70S6K, and Cell Size in Transformation and Differentiation of Hemopoietic Cells

Cited by 94 publications

References 53 publications

Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells

Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells

Efficient in vitro and in vivo gene regulation of a retrovirally delivered pro-apoptotic factor under the control of the Drosophila HSP70 promoter

Nuclear insulin receptor substrate-1 activates promoters of cell cycle progression genes

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