Int-3 Oncogene in Normal and Neoplastic Breast Development.
Final rept. 1 Sep 94-31 Aug 98
COLUMBIA UNIV NEW YORK
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To study the int-3 gene in mammary cancer, we isolated the int-3 proto-oncogene and named it Notch4, reserving the int-3 nomenclature for the oncogenic form. Notch4 is a bona-fide Notch protein. Comparison of the int-3 gene to Notch4 suggests that loss of the extracellular domain of Notch4 leads to constitutive activation of this receptor. Elongation and branching of epithelial ducts is required for mammary gland development. Branching morphogenesis of mammary TAC- 2 cells was used to examine Notch function in mammary gland development. Notch4int-3 oncoprotein inhibited branching morphogenesis induced by HGF and TGF-alpha2. Co-expression of Wnt- 1 and Notch4int-3 demonstrates that Wnt- 1 overrides the Notch-mediated inhibition of ductal morphogenesis. Wnt and Notch signaling may play opposite roles in mammary gland development. In situ hybridization revealed that Notch4 transcripts are primarily restricted to endothelial cells in embryonic and adult life, suggesting a specific role for Notch4 during development of vertebrate endothelium. In vitro as says using cultured endothelial cells suggest Notch4 activation can promote angiogenesis. We identified sel- 10, a member of the CDC4 family of proteins that promotes ubiquitination, as an int-3 binding protein.
- Anatomy and Physiology
- Medicine and Medical Research