Evidence against roles for pertussis toxin sensitive G proteins or diacylglycerol generation in insulin-like growth factor-1 stimulated DNA synthesis in MG-63 osteosarcoma cells

Linder, Barbara; Harris, Shirley; Eisen, Andrew; Nissley, Peter

doi:10.1016/0303-7207(94)90042-6

Cited by 9 publications

(6 citation statements)

References 28 publications

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“…For example, treatment with PTX was shown to exert contradictory effects on IGF-I-regulated signaling; it inhibits the IGF-I-induced mobilization of intracellular Ca 2+ in NIH3T3 cells and chondrocytes (Kanzaki et al 1997, Poiraudeau et al 1997, activation of phagocytosis in neutrophils (Jin et al 1993), and proliferation of myoblasts (Sarbassov et al 1997). In contrast, PTX treatment fails to affect other IGF-I-regulated signaling pathways, including DNA synthesis in osteosarcoma and normal rat kidney epithelial cells (Linder et al 1994, Siebler et al 1996, and mobility of melanoma cells (Stracke et al 1988). Our data demonstrated that PTX attenuates the IGF-Iregulated ERK activation and growth of human prostate epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Requirement for G proteins in insulin-like growth factor-I-induced growth of prostate cells

Lyons-Darden

Daaka

2004

Journal of Molecular Endocrinology

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Elevated levels of IGF-I in the circulation are associated with increased risk for the development of prostate cancer in men, and transgenic expression of human IGF-I in mouse epithelial prostate cells results in spontaneous prostate tumorigenesis. Little, however, is known about the mechanisms involved in the IGF-I-regulated growth of prostate cells. Here, we have demonstrated that treatment with IGF-I induces the activation of the mitogenic extracellular signal-regulated kinase (ERK) pathway and the growth of human prostate cells. Stimulation with IGF-I also promoted the tyrosine phosphorylation of epidermal growth factor receptor (EGFR). Signal relay from IGF-I to ERK requires heterotrimeric G proteins and EGFR; inhibition of Gi/o protein activation by pertussis toxin, or EGFR by tyrphostin AG1478 obliterated the ability of IGF-I to promote ERK activation. Further, treatment with pertussis toxin inhibited the IGF-I-mediated prostate cell growth. These data demonstrated the requirement of heterotrimeric G proteins in IGF-I-regulated prostate cell growth and suggest the potential utility of the G proteins as effective drug targets to combat this common cancer.

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Section: Discussionmentioning

confidence: 99%

Requirement for G proteins in insulin-like growth factor-I-induced growth of prostate cells

Lyons-Darden

Daaka

2004

Journal of Molecular Endocrinology

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“…Pertussis toxin also inhibits the activation of human neutrophil phagocytosis (35) and blocks IGF-I induced proliferation of myoblasts (33). By contrast, pertussis toxin failed to inhibit several IGF-I-dependent phenomena including GTP[S] binding to rat kidney epithelial cell membranes (36), DNA synthesis in MG-63 osteosarcoma cells (38), and IGF-I-induced human melanoma cell motility (39). We have also noted that pertussis toxin has no effect on the ability of IGF-I to protect cerebellar granule cells from apoptosis induced by removal of growth factors and low extracellular potassium (43,52).…”

Section: Discussionmentioning

confidence: 99%

Association of Heterotrimeric Gi with the Insulin-like Growth Factor-I Receptor

Hallak

Seiler

Green

et al. 2000

Journal of Biological Chemistry

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The insulin-like growth factor-I receptor (IGF-IR) is a key regulator of cell proliferation and survival. Activation of the IGF-IR induces tyrosine autophosphorylation and the binding of a series of adaptor molecules, thereby leading to the activation of MAPK. It has been demonstrated that pertussis toxin, which inactivates the G i class of GTP-binding proteins, inhibits IGF-I-mediated activation of MAPK, and a specific role for G ␤␥ subunits in IGF-I signaling was shown. In the present study, we have investigated the role of heterotrimeric G i in IGF-IR signaling in neuronal cells. Pertussis toxin inhibited IGF-I-induced activation of MAPK in rat cerebellar granule neurons and NG-108 neuronal cells. G ␣i and G ␤ subunits were associated with IGF-IR immunoprecipitates. Similarly, in IGF-IR-null mouse embryo fibroblasts transfected with the human IGF-IR, G i was complexed with the IGF-IR. G ␣s was not associated with the IGF-IR in any cell type. IGF-I induced the release of the G ␤ subunits from the IGF-IR but had no effect on the association of G ␣i . These results demonstrate an association of heterotrimeric G i with the IGF-IR and identify a discrete pool of G ␤␥ subunits available for downstream signaling following stimulation with IGF-I.Many receptors are coupled to heterotrimeric GTP-binding proteins (G-proteins). Prototypic G-protein coupled receptors (GPCRs) 1 contain a seven-membrane spanning region (1). Activated GPCRs bind to G-proteins and induce the release of G ␤␥ subunits from G ␣ subunits, which allows for the exchange of GDP for GTP on the G ␣ subunit. Activated G i subunits and G ␤␥ heterodimers interact with numerous signaling effectors, including adenylyl cyclase, ion channels, protein kinases, and phospholipases (2-4).In addition to their role in fully differentiated cells, GPCRs have been linked to mitogenesis and development (5-8). A specific role for G i in the induction of mitogenesis has been highlighted by the use of pertussis toxin, which inactivates G i by ADP-ribosylation of the G ␣ subunit. However, G ␣ subunits from several classes of G-proteins are not strongly mitogenic. Rather G ␤␥ heterodimer subunits activate a series of nonreceptor tyrosine kinases, which in turn activates p21 ras and extracellular signal-regulated kinases (or MAPK). Thus, G ␤␥ subunits serve to bridge intracellular signaling of classical GPCRs and mitogenic tyrosine kinase receptors (RTKs).G i also appears to be involved in the mitogenic actions of RTKs. Pertussis toxin variably inhibits the metabolic actions of insulin, both in vitro and in vivo (9 -16), and the insulin receptor may associate with G i (17)(18)(19). Importantly, mice with targeted knockout of G i have defects in insulin signaling (20). EGF-dependent signaling is also impaired by pertussis toxin in rat hepatocytes (21-23) and other cells (24 -27).The insulin-like growth factor-I receptor (IGF-IR), which has strong homology to the insulin receptor, exists as an ␣ 2 -␤ 2 -heterodimer and contains a cytoplasmic tyrosine kinase domain (28, 29). U...

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“…Essentially, this study showed that the IGF-I induced calcium influx and increase in DNA synthesis could be inhibited by pertussis toxin, which ADP-ribosylates the Gi/Go family of G proteins. Other reports have also suggested that several (Kanzaki et al, 1997;Poiraudeau et al, 1997;Sarbassov et al, 1997;Uehara et al, 1999), but not all (Stracke et al, 1988;Linder et al, 1994) of the actions of IGF are mediated via activation of G proteins. Recent interest in the interactions of the IGF-I receptor with heterotrimeric G proteins was rejuvenated by the demonstration that activation of extracellular signal-regulated kinases (Erks) was pertussis toxin-sensitive and mediated by G protein ␤␥ subunits (Luttrell et al, 1995).…”

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confidence: 97%

Single Transmembrane Spanning Heterotrimeric G Protein-Coupled Receptors and Their Signaling Cascades

Patel

2004

Pharmacological Reviews

101

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Evidence against roles for pertussis toxin sensitive G proteins or diacylglycerol generation in insulin-like growth factor-1 stimulated DNA synthesis in MG-63 osteosarcoma cells

Cited by 9 publications

References 28 publications

Requirement for G proteins in insulin-like growth factor-I-induced growth of prostate cells

Requirement for G proteins in insulin-like growth factor-I-induced growth of prostate cells

Association of Heterotrimeric Gi with the Insulin-like Growth Factor-I Receptor

Single Transmembrane Spanning Heterotrimeric G Protein-Coupled Receptors and Their Signaling Cascades

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