Ras proteins are essential and selective for the action of insulin-like growth factor 1 late in the G1 phase of the cell cycle in BALB/c murine fibroblasts.

Lu, Kuang‐Hui; Campisi, Judith

doi:10.1073/pnas.89.9.3889

Cited by 58 publications

(26 citation statements)

References 31 publications

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“…Both c-Src and c-Ras have been implicated as cellular effectors of activated growth factor receptors, including the receptors for PDGF (24,42) and EGF (8,31). Indeed, Src may play a role in exit from G 0 and completion of G 1 (56), and Ras is thought to be necessary for the traverse of G 1 in BALB/c-3T3 cells (30). By contrast with their cellular proto-oncogene counterparts, v-src and v-ras encode mutant proteins that deliver constitutive mitogenic signals, even in the absence of growth factor receptor activation.…”

Section: Resultsmentioning

confidence: 99%

Repression of Platelet-Derived Growth Factor β-Receptor Expression by Mitogenic Growth Factors and Transforming Oncogenes in Murine 3T3 Fibroblasts

Vaziri

Faller

1995

Molecular and Cellular Biology

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Platelet-derived growth factor BB (PDGF-BB) is an important extracellular factor for regulating the G 0 -S phase transition of murine BALB/c-3T3 fibroblasts. We have investigated the expression of the PDGF ␤ receptor (PDGF␤R) in these cells. We show that the state of growth arrest in G 0 , resulting from serum deprivation, is associated with increased expression of the PDGF␤R. When the growth-arrested fibroblasts are stimulated to reenter the cell cycle by the mitogenic action of serum or certain specific combinations of growth factors, PDGF␤R mRNA levels and cell surface PDGF-BB-binding sites are markedly downregulated. Oncogene-transformed 3T3 cell lines, which fail to undergo growth arrest following prolonged serum deprivation, express constitutively low levels of the PDGF␤R mRNA and possess greatly reduced numbers of cell surface PDGF receptors, as determined by PDGF-BB binding and Western blotting (immunoblotting). Nuclear runoff assays indicate the mechanism of repression of PDGF␤R expression to be, at least in large part, transcriptional. These data indicate that expression of the PDGF␤R is regulated in a growth state-dependent manner in fibroblasts and suggest that this may provide a means by which cells can modulate their responsiveness to the actions of PDGF.

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Section: Resultsmentioning

confidence: 99%

Repression of Platelet-Derived Growth Factor β-Receptor Expression by Mitogenic Growth Factors and Transforming Oncogenes in Murine 3T3 Fibroblasts

Vaziri

Faller

1995

Molecular and Cellular Biology

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“…The activation of MAPK3/1 peaked from 15 to 30 min after the IGF1 stimulation. Earlier studies using fibroblasts indicated that RAS-MAP2K-MAPK3/1 activation is important in IGF1-related cell proliferation (Lu & Campisi 1992, Jhun et al 1994, Sasaoka et al 1996. In experiments using gynecological cancer cell lines, such as a cervical carcinoma cell line (SiHa) and an ovarian carcinoma cell line (OVCR3), IGF1 was reported to transmit the signal possibly via the MAPK3/1 pathway (Shen et al 2004).…”

Section: Endocrine-related Cancermentioning

confidence: 99%

Autocrine stimulation of IGF1 in estrogen-induced growth of endometrial carcinoma cells: involvement of the mitogen-activated protein kinase pathway followed by up-regulation of cyclin D1 and cyclin E

Kashima¹,

Shiozawa²,

Miyamoto³

et al. 2009

Endocrine-Related Cancer

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To examine estrogen-induced growth mechanisms of endometrial carcinoma, we investigated the estrogen-induced activation of the mitogen-activated protein kinase (MAPK) pathway and cell cycle regulators. Estradiol (E 2 ) treatment at concentrations of 10 K8 M and 10 K6 M to estrogen receptor (ER)-positive endometrial carcinoma Ishikawa cells for 24 h resulted in increased cell proliferation by 20% and 28% respectively. The E 2 -induced proliferation was associated with the activation of extracellular signal-regulated kinase (MAPK)3/1 and up-regulation of cyclin D1 and E, which were suppressed by the addition of an MAP2K inhibitor (U0126) or an ER antagonist (ICI 182 780). Then, our screening for estrogen-inducible growth factors identified that IGF1 was up-regulated remarkably by E 2 . Immunoprecipitation using conditioned medium of Ishikawa cells after E 2 treatment confirmed the E 2 -induced secretion of IGF1 protein. Treatment with recombinant IGF1 stimulated cell proliferation in a dose-dependent fashion, in association with MAPK3/1 phosphorylation and up-regulation of cyclin D1 and E. These IGF1-induced responses were suppressed by treatment with MAP2K inhibitor or anti-IGF1 receptor antibody. Immunohistochemical staining confirmed the expression of activated MAPK3/1 in normal proliferative phase endometria and endometrial carcinomas, indicating the involvement of this pathway in actively proliferating endometrial tissues in vivo. These findings suggest that E 2 -induced proliferation of endometrial carcinoma cells is mediated by the MAPK3/1 pathway via autocrine stimulation of IGF1.

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“…Activation of both PI3K and MAPK pathways can induce proliferation in MCF7 cells (Lu & Campisi 1992, Jhun et al 1994, Dufourny et al 1997. As Lantus strongly phosphorylated and thus activated key signaling proteins of both pathways (Figs 2 and 3), we were interested in studying the role of either of the pathways in the proliferative ability of Lantus.…”

Section: Lantus Induced Proliferation In Mcf7 Cells Is Mainly Due To mentioning

confidence: 99%

Analysis of signaling pathways related to cell proliferation stimulated by insulin analogs in human mammary epithelial cell lines

Shukla¹,

Grisouard²,

Ehemann³

et al. 2009

Endocrine-Related Cancer

120

125

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Insulin and insulin analogs stimulate proliferation of human mammary epithelial cells. We identified and analyzed the signaling pathways related to cell proliferation induced by regular insulin and by four insulin analogs presently approved for therapeutical use. Benign and malignant mammary cell lines showing different insulin receptor (IR) and IGF-I receptor (IGF-IR) expression patterns were studied. Cell proliferation was studied by crystal violet staining (BrdU-FACS analysis). Activation of insulin and IGF signaling pathways was studied by analysis of the phosphorylation status of IGF-IR and of key signaling proteins of the phosphoinositide 3-kinase (PI3K)/Akt and MAP kinase pathways, by the use of specific PI3K and MAP kinase inhibitors, and by silencing of IR and IGF-IR. Lantus stimulated the growth of MCF7 cells, which show high IGF-IR/IR ratio, significantly at 0.3 nmol/l, while regular insulin (Actrapid and bovine insulin) and other insulin analogs (Novorapid, Humalog, and Levemir) stimulated cell growth at 1.5-15 nmol/l concentrations. No difference between Lantus and the other insulin analogs was observed regarding growth stimulation of MCF10A cells showing low IGF-IR/IR ratio. Growth stimulation of MCF7 cells by Lantus was mainly due to strong activation of the IGF-IR and the MAP kinase pathway. Regular insulin and other insulin analogs tested activated mainly the IR and the PI3K/Akt pathway. We conclude that unlike regular insulin and other insulin analogs, Lantus strongly activates the IGF-IR and the MAP kinase pathway in MCF7 cells and is a strong mitogen for cells characterized by a high-IGF-IR/IR ratio.

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Ras proteins are essential and selective for the action of insulin-like growth factor 1 late in the G1 phase of the cell cycle in BALB/c murine fibroblasts.

Cited by 58 publications

References 31 publications

Repression of Platelet-Derived Growth Factor β-Receptor Expression by Mitogenic Growth Factors and Transforming Oncogenes in Murine 3T3 Fibroblasts

Repression of Platelet-Derived Growth Factor β-Receptor Expression by Mitogenic Growth Factors and Transforming Oncogenes in Murine 3T3 Fibroblasts

Autocrine stimulation of IGF1 in estrogen-induced growth of endometrial carcinoma cells: involvement of the mitogen-activated protein kinase pathway followed by up-regulation of cyclin D1 and cyclin E

Analysis of signaling pathways related to cell proliferation stimulated by insulin analogs in human mammary epithelial cell lines

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