Blocking of EGF-Dependent Cell Proliferation by EGF Receptor Kinase Inhibitors

Yaish, Pnina; Gazit, Aviv; Gilon, Chaim; Levitzki, Alexander

doi:10.1126/science.3263702

Cited by 564 publications

(277 citation statements)

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“…A large majority of astrocytes were sensitive to TGFa mitogenic effects in our cultures with 80% of cells having entered the cell cycle at 3 days (Figure 5b). Finally, AG1478, a specific inhibitor of erbB1 tyrosine kinase activity (Yaish et al, 1988) abolished TGFainduced proliferation as observed at 7 DIV (percentage of BrdU-immunoreactive nuclei over total nuclei numbers labelled with hematoxylin: untreated, 18.371.8; AG1478-treated, 1171.2; TGFa-treated, 70.671; TGFa plus AG1478-treated, 13.470.8, mean7s.e.m., n ¼ 4). To evaluate the transduction pathways underlying this mitogenic effect, astrocytes were treated with TGFa in the additional presence of U0126, a specific inhibitor of both MEK1 and MEK2 kinase activities, which prevents phosphorylation, and thus activation of ERK1/2 (Favata et al, 1998).…”

Section: Resultsmentioning

confidence: 89%

Transforming growth factor alpha acts as a gliatrophin for mouse and human astrocytes

et al. 2006

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Astrocyte death has been implicated in several neuropathological diseases, but the identification of molecules susceptible of promoting astrocyte survival has been elusive. We investigated whether transforming growth factor alpha (TGFa), an erbB1/EGFR ligand, which promotes glioma progression and affects astrocyte metabolism at embryonic and adult stages, regulates astrocyte survival. Primary serum-free astrocyte cultures from postnatal mouse and fetal human cortices were used. Transforming growth factor alpha protected both species of astrocytes from staurosporine-induced apoptosis. In serum-free medium, mouse astrocytes did not survive beyond 2 months while TGFa-treated astrocytes survived up to 12 months. Transforming growth factor alpha also promoted long-term survival of human astrocytes. We additionally extended TGFa proliferative effects to human astrocytes. After 3 days of permanent application, TGFa induced a major downregulation of both erbB1 and erbB2. This downregulation did not impair the functional activation of the receptors, as ascertained by their tyrosine phosphorylation and the continuous stimulation of both ERK/MAPK and PI3K/Akt pathways up to 7 days, the longest time examined. The full cellular effects of TGFa required activation of both transduction pathways. Enhanced proliferation and survival thus define TGFa as a gliatrophin for mammalian astrocytes. These results demonstrate that in normal, non-transformed astrocytes, sustained and functional erbBs activation is achieved without bypassing ligand-induced receptors downregulation.

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Section: Resultsmentioning

confidence: 89%

Transforming growth factor alpha acts as a gliatrophin for mouse and human astrocytes

et al. 2006

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“…RG 50864 belongs to a family of arylidene derivatives recently described to inhibit the tyrosine kinase activity of the EGF receptor at concentrations 1/100th to 1/700th the concentration needed to block tyrosine kinase of the insulin receptor (25). Like insulin, EGFs mechanism of action involves both autophosphorylation of its receptor and tyrosine phosphorylation of a variety of cellular target proteins (32).…”

Section: Discussionmentioning

confidence: 99%

“…In all experiments the MEs were preincubated for 15 min, then for 30 min after a change of medium, and finally for 2 h with the growth factors of interest. At the end of this period, the medium was removed and assayed for LHRH and PGE2 as reported (24 (25). The inhibitor was initially dissolved in ethanol and then diluted in the incubation medium to a final concentration of 60 ,tM, which was present throughout the entire incubation period.…”

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confidence: 99%

Involvement of transforming growth factor alpha in the release of luteinizing hormone-releasing hormone from the developing female hypothalamus.

Ojeda

Urbanski

Costa

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

157

121

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Little is known about the presence of trophic factors in the hypothalamus and the role they may play in regulating the functional development of hypothalamic neurons. We have investigated the ability of epidermal growth factor (EGF) and transforming growth factor a (TGF-a) to affect the release of luteinizing hormone-releasing hormone (LHRH), the neuropeptide that controls reproductive development. We have also determined whether the genes encoding EGF and TGF-a are expressed in the prepubertal female hypothalamus. Northern blot analysis of poly(A)+ RNA utilizing a single-stranded EGF cDNA probe failed to reveal the presence of EGF mRNA in either the hypothalamus or the cerebral cortex at any age studied (fetal day 18 to postnatal day 36). In contrast, both a complementary RNA probe and a double-stranded TGF-a cDNA recognized in these regions a 4.5-kilobase (kb) mRNA species identical to TGF-a mRNA. The abundance of TGF-a mRNA was 3-4 times greater in the hypothalamus than in the cerebral cortex. Both EGF and TGF-a (2-100 ng/ml) elicited a dose-related increase in LHRH release from the median eminence ofjuvenile rats in vitro. They also enhanced prostaglandin E2 (PGE2) release. The transforming growth factors TGF-fi, and -P2 were ineffective. Only a high dose of basic fibroblast growth factor was able to increase LHRH and PGE2 release. Blockade of the EGF receptor transduction mechanism with RG 50864, a selective inhibitor of EGF receptor tyrosine kinase activity, prevented the effect of both EGF and TGF-a on LHRH and PGE2 release but failed to inhibit the stimulatory effect of PGE2 on LHRH release. Inhibition of prostaglandin synthesis abolished the effect of TGF-et on LHRH, indicating that PGE2 mediates TGF-ainduced LHRH release. The results indicate that the effect of EGF and TGF-a on LHRH release is mediated by the EGF/TGF-a receptor and suggest that TGF-a rather than EGF may be the physiological ligand for this interaction. Since in the central nervous system most EGF/TGF-a receptors are located on glial cells, the results also raise the possibility that-at the median eminence-TGF-a action may involve a glial-neuronal interaction, a mechanism by which the trophic factor first stimulates PGE2 release from glial cells, and then PGE2 elicits LHRH from the neuronal terminals.

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“…One such class of TK inhibitors, referred to as tyrphostins, was reported in the late 1980s (Yaish et al, 1988). Synthesised and developed by a team in Israel, this novel class of compounds was one of the first to demonstrate p210 BCR -ABL TK inhibitory properties, inducing cell kill in K562 cells (Anafi et al, 1993).…”

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confidence: 99%

The in vitro activity of the tyrosine kinase inhibitor STI571 in BCR–ABL positive chronic myeloid leukaemia cells: synergistic interactions with anti-leukaemic agents

2002

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Chronic myeloid leukaemia is typically characterised by the presence of dysregulated BCR -ABL tyrosine kinase activity, which is central to the oncogenic feature of being resistant to a wide range of cytotoxic agents. We have investigated whether the inhibition of this tyrosine kinase by the novel compound STI571 (formerly CGP57148B) would render K562, KU812 cell lines and chronic myeloid leukaemia-progenitor cells sensitive to induction of cell kill. Proliferation assays showed STI571 to be an effective cytotoxic agent in chronic myeloid leukaemia-derived cell lines (IC 50 on day 5 of 4.6 mg ml 71 and 3.4 mg ml 71 for K562 and KU812 respectively) and in leukaemic blast cells (per cent viability on day 3 at 4 mg ml 71 : 55.5+8.7 vs 96.4+3.7%). STI571 also appeared to specifically target bcr -abl expressing cells, as results from colony forming assays using the surviving cell fraction from STI571-treated peripheral CD34 + chronic myeloid leukaemia blast cells, indicated a reduction in the expansion of colonies of myeloid lineage, but no effect on normal colony formation. Our data also showed synergy between STI571 and other anti-leukaemic agents; as an example, there were significant increases in per cent cell kill in cell lines cultured with both STI571 and etoposide compared to the two alone (per cent cell kill on day 3: 73.7+11.3 vs 44.5+8.7 and 17.8+7.0% in cultures with STI571 and etoposide alone respectively; P50.001). This study confirms the central oncogenic role of BCR -ABL in the pathogenesis of chronic myeloid leukaemia, and highlights the role of targeting this tyrosine kinase as a useful tool in the clinical management of the disease.

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Blocking of EGF-Dependent Cell Proliferation by EGF Receptor Kinase Inhibitors

Cited by 564 publications

References 16 publications

Transforming growth factor alpha acts as a gliatrophin for mouse and human astrocytes

Transforming growth factor alpha acts as a gliatrophin for mouse and human astrocytes

Involvement of transforming growth factor alpha in the release of luteinizing hormone-releasing hormone from the developing female hypothalamus.

The in vitro activity of the tyrosine kinase inhibitor STI571 in BCR–ABL positive chronic myeloid leukaemia cells: synergistic interactions with anti-leukaemic agents

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