A mitochondrial protein, Bit1, mediates apoptosis regulated by integrins and Groucho/TLE corepressors.
A delicate balance of signals regulates cell survival. One set of these signals is derived from integrin-mediated cell adhesion to the extracellular matrix (ECM). Loss of cell attachment to the ECM causes apoptosis, a process known as anoikis. In searching for proteins involved in cell adhesion-dependent regulation of anoikis, we identified Bit1, a mitochondrial protein that is released into the cytoplasm during apoptosis. Cytoplasmic Bit1 forms a complex with AES, a small Groucho/transducin-like enhancer of split (TLE) protein, and induces cell death with characteristics of caspase-independent apoptosis. Cell attachment to fibronectin counteracts the apoptotic effect of Bit1 and AES. Increasing Bit1 expression enhances anoikis, while suppressing the expression reduces it. Thus, we have elucidated an integrin-controlled pathway that is, at least in part, responsible for the cell survival effects of cell-ECM interactions.
Cancer Research Center, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Yiwen
Y
Jan
Michelle
M
Matter
Jih-tung
JT
Pai
Yen-Liang
YL
Chen
Jan
J
Pilch
Masanobu
M
Komatsu
Edgar
E
Ong
Minoru
M
Fukuda
Erkki
E
Ruoslahti
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins; D002265:Carboxylic Ester Hydrolases; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D056970:Co-Repressor Proteins; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D051792:Basic Helix-Loop-Helix Proteins; D002265:Carboxylic Ester Hydrolases; D020169:Caspases; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D016023:Integrins; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; C499043:TLE1 protein, human; C498445:TLE5 protein, human; C091023:gro protein, Drosophila; C483418:PTH2 protein, human