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Targeted deletion of the suppressor gene bin1/amphiphysin2 accentuates the neoplastic character of transformed mouse fibroblasts.

Authors
  • Muller, Alexander J
  • DuHadaway, James B
  • Donover, P Scott
  • Sutanto-Ward, Erika
  • Prendergast, George C
Type
Published Article
Journal
Cancer biology & therapy
Publication Date
Dec 01, 2004
Volume
3
Issue
12
Pages
1236–1242
Identifiers
PMID: 15611650
Source
Medline
License
Unknown

Abstract

The Bin1/Amphiphysin2 gene encodes several alternately spliced BAR adapter proteins that have been implicated in membrane-associated and nuclear processes. Bin1 expression is often attenuated during tumor progression and Bin1 splice isoforms that localize to the nucleus display tumor suppressor properties. While these properties may reflect the ability of these isoforms to interact with and suppress the cell transforming activity of c-Myc, the effects of Bin1 deletion on the oncogenicity of c-myc or other transforming genes has not been gauged directly. Here we report that targeted deletion of Bin1 enhances the neoplastic character of primary murine embryo fibroblasts (MEFs) cotransformed by c-myc and mutant grasg. Specifically, Bin1 loss accentuated the spindle morphology of transformed cells, increased anchorage-independent proliferation, and promoted tumor formation in syngeneic hosts. These effects were specific as they were not recapitulated in cells transformed by viral oncoproteins and mutant ras. Although some Bin1 splice isoforms associate with endocytotic complexes the effects of Bin1 loss were not correlated with a generalized defect in receptor-mediated endocytosis. However, Bin1 loss increased sensitivity to paclitaxel, a drug that can affect endocytotic trafficking by disrupting microtubule dynamics. In E1A?transformed MEFs, Bin1 loss reduced the susceptibility to apoptosis triggered by tumor necrosis factor-alpha, an effect that was associated with precocious nuclear trafficking of NF-kappaB. These findings offer a novel line of support for the hypothesized role of Bin1 in limiting malignant growth, possibly as a negative modifier or anti-progression gene.

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