Kit and PDGFR-α activities are necessary for Notch4/Int3-induced tumorigenesis

A. Raafat, A. Zoltan-Jones, Luigi Strizzi, S. Bargo, K. Kimura, D. Salomon, R. Callahan*

*Corresponding author for this work

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Transgenic mice overexpressing Notch4 intracellular domain (Int3) under the control of the whey acidic protein (WAP) or mouse mammary tumor virus-long terminal repeat promoters, develop mammary tumors. Microarray analysis of these tumors revealed high levels of c-Kit expression. Gleevec is a tyrosine kinase inhibitor that targets c-Kit, platelet-derived growth factor receptors (PDGFRs) and c-Abl. This led us to speculate that tyrosine kinase receptor activity might be a driving force in the development of Int3 mammary tumors. WAP-Int3 tumor-bearing mice were treated with continuous release of Gleevec using subcutaneously implanted Alzet pumps. Phoshorylation of c-Kit, PDGFRs and c-Abl is inhibited in Int3 transgenic mammary tumors by Gleevec. Inhibition of these enzymes is associated with a decrease in cell proliferation and angiogenesis, and an induction of apoptosis. To examine the signaling mechanisms underlying Notch4/Int3 tumorigenesis, we employed small interfering RNA (siRNA) to knock down c-Kit, PDGFRs and c-Abl alone or in combination and observed the effects on soft agar growth of HC11 cells overexpressing Int3. Only siRNA constructs for c-Kit and/or PDGFR-α were able to inhibit HC11-Int3 colony formation in soft agar. Our data demonstrate an inhibitory effect of Gleevec on Int3-induced transformation of HC11 cells and mammary tumors and indicate an oncogenic role for c-Kit and PDGFR-α tyrosine kinases in the context of Int3 signaling.

Original languageEnglish (US)
Pages (from-to)662-672
Number of pages11
JournalOncogene
Volume26
Issue number5
DOIs
StatePublished - Feb 1 2007

Keywords

  • Gleevec
  • Kit
  • Notch4/Int3
  • PDGFR-α
  • Phosphorylation
  • siRNA

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Raafat, A., Zoltan-Jones, A., Strizzi, L., Bargo, S., Kimura, K., Salomon, D., & Callahan, R. (2007). Kit and PDGFR-α activities are necessary for Notch4/Int3-induced tumorigenesis. Oncogene, 26(5), 662-672. https://doi.org/10.1038/sj.onc.1209823