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A human brain tumor-derived PDGFR-α deletion mutant is transforming

Oncogene volume 22, pages 722–733 (2003)Cite this article

Abstract

Aberrant receptor tyrosine kinase signaling plays an important role in the molecular pathogenesis of brain tumors. We have been studying a previously identified human glioblastoma-derived PDGFR-α mutant that has an in-frame deletion in the extracellular domain, causing loss of exons 8 and 9 (PDGFR-αΔ8,9). In the primary tumor, this deletion mutant receptor was shown to be amplified and overexpressed. The purpose of this study was to determine the expression, activity, localization, and transformation properties of this deletion mutant. In the absence of serum, or PDGF-AA, PDGFR-αΔ8,9 was phosphorylated on tyrosine residues, indicating ligand-independent autoactivation. Localization by staining and cell surface biotinylation studies revealed expression of the deletion mutant predominantly in the cytoplasm, with very little present on the cell surface. To determine if PDGFR-αΔ8,9 was oncogenic, we transfected wild-type and mutant receptors into Rat1 cells and performed analyses of cell growth, in vitro transformation, and subcutaneous growth in the nude mouse. PDGFR-αΔ8,9-expressing cells displayed enhanced cell growth and survival in low serum, and formed foci in monolayer cultures. PDGFR-αΔ8,9-expressing Rat1 cells were also tumorigenic when injected subcutaneously into nude mice. Expression of PDGFR-αΔ8,9 was also associated with increased c-Jun phosphorylation in the absence of PDGF ligand, demonstrating also that the mutant receptor is associated with altered intracellular signaling. These data demonstrate that PDGFR-αΔ8,9 is transforming, and it is the first demonstration of a naturally occurring tumor-derived mutant PDGFR-α with oncogenic properties.

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Acknowledgements

Dr Dirks' research was supported by the National Cancer Institute of Canada with funds from the Terry Fox Run, from the Arthur and Sonia Labatt Brain Tumor Research Center at the Hospital for Sick Children, and from the Hospital for Sick Children Research Institute. We are grateful to Dr Tokuo Yamamoto from Tohoku University, Japan, for the wild-type and PDGFR-αΔ8,9 cDNAs. We thank Dr Sean Egan and Dr Jane McGlade for helpful discussions and critical reading of the manuscript.

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  1. Division of Neurosurgery and Program in Developmental Biology,Arthur and Sonia Labatt Brain Tumor Research Laboratory, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

    I D Clarke & P B Dirks

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Correspondence to P B Dirks.

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Clarke, I., Dirks, P. A human brain tumor-derived PDGFR-α deletion mutant is transforming. Oncogene 22, 722–733 (2003). https://doi.org/10.1038/sj.onc.1206160

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