BimEL is an important determinant for induction of anoikis sensitivity by mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitors

Hidesuke Fukazawa, Kohji Noguchi, Atsuko Masumi, Yuko Murakami, Yoshimasa Uehara

研究成果: Article査読

36 被引用数 (Scopus)

抄録

Loss of contact with substratum triggers apoptosis in many normal cell types, a phenomenon termed anoikis. We reported previously that mitogen-activated protein/ extracellular signal-regulated kinase kinase (MEK) inhibitors induced apoptosis in nonanchored MDA-MB231 and HBC4 human breast cancer cells, whereas anchored cells remained viable. Here, we report that activation of the BH3-only protein BimEL is the major mechanism for induction of anoikis sensitivity by MEK inhibitors in MDA-MB231 and HBC4 cells. On treatment with MEK inhibitors, BimEL in MDA-MB231 and HBC4 cells rapidly increased, irrespective of the state of anchorage. However, it translocated to mitochondria only in nonanchored cells, explaining why attached cells remain viable. MDAMB231 and HBC4 cells had exceedingly low basal levels of BimEL compared with other breast cancer cells, suggesting that maintenance of low BimEL amount is important for survival of these cells. MEK inhibitors also induced the electrophoretic mobility shift of BimEL, indicative of reduced phosphorylation. In vitro, BimEL was phosphorylated by extracellular signal-regulated kinase on Ser69, which resides in the BimEL-specific insert region. Using phosphospecific antibody against this site, we show that this residue is actually phosphorylated in cells. We also show that phosphorylation of Ser69 promotes ubiquitination of BimEL. We conclude that MEK inhibitors sensitize MDA-MB231 and HBC4 cells to anoikis by blocking phosphorylation and hence degradation of BimEL, a mechanism that these cells depend on to escape anoikis.

本文言語English
ページ(範囲)1281-1288
ページ数8
ジャーナルMolecular cancer therapeutics
3
10
出版ステータスPublished - 2004 10月 1

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究

フィンガープリント

「BimEL is an important determinant for induction of anoikis sensitivity by mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitors」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル