Cyclophilin A as negative regulator of apoptosis by sequestering cytochrome c.
The release of cytochrome c from the mitochondrial intermembrane space is a decisive event in programmed cell death. Once in the cytoplasm, cytochrome c is involved in the formation of the macromolecular complex termed apoptosome, which activates procaspase-9 which in turn activates downstream procaspase-3. There are increasing evidence indicating that cyclophilin A is highly expressed in many tumors and cell lines where it exerts an anti-apoptotic function. In brain tissue, which over-expresses constitutively cyclophilin A, we found mixed dimers composed of cyclophilin A and cytochrome c. In a cell-free system we observed that pure cyclophilin A inhibited cytochrome c-dependent procaspase-3 activation. Moreover, we detected cyclophilin A-cytochrome c complexes within the cytoplasm of HCT116 cells following staurosporine-induced apoptosis. Our results strongly support that, in tumor cells, cyclophilin A is able to inhibit procaspase-3 activation by sequestering cytochrome c.
Bonfils
Claude
C
IRCM, INSERM U, UM1, CRLC Val d'Aurelle-Paul Lamarque, Montpellier, France. claude.bonfils@valdorel.fnclcc.fr
Bec
Nicole
N
Larroque
Christian
C
Del Rio
Maguy
M
Gongora
Céline
C
Pugnière
Martine
M
Martineau
Pierre
P
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000201:enzymology*; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D021984:Cyclophilin A / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000201:enzymology*; D009474:Neurons / Q000201:enzymology
D061945:Caspase Inhibitors; D045304:Cytochromes c; D021984:Cyclophilin A