The IGF-I Receptor in Mitogenesis and Transformation of Mouse Embryo Cells: Role of Receptor Number

Rubini, Michele; Hongo, Atsushi; D'Ambrosio, Consuelo; Baserga, Renato

doi:10.1006/excr.1996.3430

Cited by 110 publications

(98 citation statements)

References 39 publications

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“…This is the first in vivo demonstration that overexpression of WT IGF-IR is sufficient to induce mammary epithelial transformation. This observation is consistent with the ability of IGF-IR to transform cells in culture (Rubini et al, 1997;Butler et al, 1998).…”

Section: Discussionsupporting

confidence: 83%

Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation

et al. 2006

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Overexpression and hyperactivation of the type I insulinlike growth factor receptor (IGF-IR) has been observed in human breast tumor biopsies. In addition, in vitro studies indicate that overexpression of IGF-IR is sufficient to transform cells such as mouse embryo fibroblasts and this receptor promotes proliferation and survival in breast cancer cell lines. To fully understand the function of the IGF-IR in tumor initiation and progression, transgenic mice containing human IGF-IR under a doxycyclineinducible MMTV promoter system were generated. Administration of 2 mg/ml doxycycline in the animals' water supply beginning at 21 days of age resulted in elevated levels of IGF-IR in mammary epithelial cells as detected by Western blotting and immunohistochemistry. Whole mount analysis of 55-day-old mouse mammary glands revealed that IGF-IR overexpression significantly impaired ductal elongation. Moreover, histological analyses revealed multiple hyperplasic lesions in the mammary glands of these 55-day-old mice. The formation of palpable mammary tumors was evident at approximately 2 months of age and was associated with increased levels of IGF-IR signaling molecules including phosphorylated Akt, Erk1/Erk2 and STAT3. Therefore, these transgenic mice provide evidence that IGF-IR overexpression is sufficient to induce mammary epithelial hyperplasia and tumor formation in vivo and provide a model to further understand the function of IGF-IR in mammary epithelial transformation.

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Section: Discussionsupporting

confidence: 83%

Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation

et al. 2006

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“…Even though PPP-mediated IGF-1R downregulation was moderate (30-50% after 12 h treatment of cultured cells and 50% in vivo), it is probably sufficient to contribute to tumor regression. Rubini et al (1997) showed namely that as many as 30 000 IGF-1 receptors per cell was a minimum for anchorage independent growth. Therefore, a 50% reduction of IGF-1R number in tumors is likely to be below this critical level.…”

Section: Discussionmentioning

confidence: 99%

Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor: potential mechanistic involvement of Mdm2 and β-arrestin1

Vasilcanu

Rosengren

et al. 2007

Oncogene

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The insulin-like growth factor 1 receptor (IGF-1R) is crucial for growth and survival of malignant cells. Experience in targeting IGF-1R in cancer models has shown that strategies promoting downregulation of the receptor are much more efficient in inducing apoptosis than those inhibiting the IGF-1R activity. Recently, we found that the cyclolignan picropodophyllin (PPP) inhibits phosphorylation of IGF-1R and activation of downstream signaling without interfering with the highly homologous insulin receptor (IR). Furthermore, PPP treatment caused strong regression of tumor grafts and prolonged survival of animals with systemic tumor disease. Here we demonstrate that PPP also downregulates the IGF-1R, whereas the IR and several other receptors were not affected. PPP-induced IGF-1R downregulation required expression of the MDM2 E3 ligase, which recently was found to ubiquitinate and cause degradation of the IGF-1R. In addition knockdown of barrestin1, the adaptor molecule known to bridges MDM2 and IGF-1R, prevented downregulation of the receptor and significantly decreased PPP-induced cell death. All together these data suggest that PPP downregulates IGF-1R by interfering with the action of b-arrestin1/MDM2 as well as the achieved receptor downregulation contributes to the apoptotic effect of PPP.

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“…Our results (Figure 3) suggest that the IGF-IR and IRS-1 proteins detected in mouse and human medulloblastoma cell lines are expressed at levels (Reiss et al, 1998b;Rubini et al, 1997) that ought to support cell proliferation and survival. In fact, Figure 5 shows that medulloblastoma cell lines are indeed able to proliferate when stimulated solely with IGF-I.…”

Section: Igf-i-dependent Growth and Survival Of Medulloblastoma Cell mentioning

confidence: 75%

“…As shown in Figure 3a,b, IGF-IR proteins were present in all mouse and human medulloblastoma cell lines, ranging from about 2610 4 to 4610 4 IGF-IR molecules per cell. These values were estimated on the basis of the IGF-IR protein levels in R600 cells that are known to express 3610 4 IGF-IR molecules per cell (Reiss et al, 1998b;Rubini et al, 1997), and have been repeatedly used in semiquantitative assays of IGF-IR levels in cells and tissues (Reiss et al, 1998a(Reiss et al, ,b, 1999. Levels of the IGF-IR in mouse medulloblastoma cell lines were only slightly altered when compared with control mouse cerebellar tissue.…”

Section: Levels Of Igf-ir Irs-1 and Pi3-k In Medulloblastoma Cell Lmentioning

confidence: 99%

Activation of the IGF-IR system contributes to malignant growth of human and mouse medulloblastomas

et al. 2001

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The IGF-I Receptor in Mitogenesis and Transformation of Mouse Embryo Cells: Role of Receptor Number

Cited by 110 publications

References 39 publications

Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation

Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation

Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor: potential mechanistic involvement of Mdm2 and β-arrestin1

Activation of the IGF-IR system contributes to malignant growth of human and mouse medulloblastomas

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