Regulation by Gi2 proteins of v-fms-induced proliferation and transformation via Src-kinase and STAT3 (original) (raw)

• Original Paper
• Published: 18 November 1999

Oncogene volume 18, pages 6335–6342 (1999)Cite this article

Abstract

We previously showed that Gi2 proteins interfere with the transduction of CSF-1 receptor (CSF-1R) proliferation signals (Corre and Hermouet, 1995). To identify CSF-1R pathways controlled by Gi2, we transfected **v**-fms, the oncogenic equivalent of CSF-1R, in NIH3T3 cells in which Gi2 proteins were inactivated by stably expressing a dominant negative mutant form of the α subunit of Gi2 (αi2-G204A). Expression of αi2-G204A resulted in decreased Src-kinase activity, delayed activation of p42 ERK-MAPK, decreased cyclin D1 expression and reduced proliferation in response to serum. In αi2-G204A cells transfected with **v-fms, Src-kinase activity remained deficient but p42 MAPK activity and cyclin D1 expression were similar to those of vector/v**-fms cells, suggesting that **v-fms bypasses Src to activate the ERK-MAPK cascade. However, DNA synthesis and focus formation were inhibited by up to 80% in αi2-G204A/v-fms cells compared to vector/v-fms cells. We found that tyrosine phosphorylation of STAT3, also activated by CSF-1R/v-fms, was inhibited in αi2-G204A/v**-fms cells; in addition, expression of an 85 kDa, C-terminal truncated form of STAT3 (STAT3Δ) was constitutively increased. Both the inhibition of **v**-fms-induced STAT3 tyrosine phosphorylation and the increased expression of STAT3Δ were reproduced by transfecting a dominant negative mutant of Src. Last, we show that expression of STAT3Δ55C, a mutant form of STAT3 lacking the last 55 C-terminal amino acids, is sufficient to inhibit DNA synthesis and **v-fms-induced transformation in NIH3T3 cells. In summary, adequate regulation by Gi2 proteins of the activity of both Src-kinase and STAT3 is required for optimal cell proliferation in response to CSF-1R/v**-fms.

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Acknowledgements

We thank Elisabeth André for expert technical help in cell transfections. This work was supported by grants from La Ligue Nationale contre le Cancer (Comité National et Comités Départementaux de Vendée, de Loire-Atlantique et du Morbihan) and the Association pour la Recherche contre le Cancer (ARC). Isabelle Corre was the recipient of a fellowship from La Ligue Nationale contre le Cancer (Comité des Cótes d'Armor).

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Authors and Affiliations

1. Groupe `Cytokines, Récepteurs et Transduction de Signal', INSERM U463, Institut de Biologie, 9, Quai Moncousu, 44093, Nantes, France
   Isabelle Corre & Sylvie Hermouet
2. Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York, USA
   Heinz Baumann

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1. Isabelle Corre
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2. Heinz Baumann
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3. Sylvie Hermouet
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Corre, I., Baumann, H. & Hermouet, S. Regulation by Gi2 proteins of **v**-fms-induced proliferation and transformation via Src-kinase and STAT3.Oncogene 18, 6335–6342 (1999). https://doi.org/10.1038/sj.onc.1203010

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• Received: 17 December 1998
• Revised: 27 May 1999
• Accepted: 03 June 1999
• Published: 18 November 1999
• Issue Date: 04 November 1999
• DOI: https://doi.org/10.1038/sj.onc.1203010

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