Regulation of mitochondrial Smac/DIABLO-selective release by survivin.
The intrinsic apoptotic pathway is characterized by the release of several mitochondrial intermembrane proteins into the cytosol of dying cells. It is unclear whether the release of these proteins follows a common or specific pathway. In the present report we show that survivin and, to a lesser extent, the survivin splice variant survivin DeltaEx3 regulate the specific liberation of second mitochondria-derived activator of caspase/direct IAP binding protein with low pI (Smac/DIABLO), an inhibitor of apoptosis proteins binding protein, during apoptosis induced by etoposide, a DNA damaging agent. This antineoplastic drug induced posttranscriptional upregulation of survivin and survivin DeltaEx3. In turn, mitochondrial survivin associated with Smac/DIABLO, delaying its release. In addition, cytosolic survivin also stabilized the cytosolic levels of released Smac/DIABLO. These results provide an explanation for the observed differences in the release of mitochondrial intermembrane proteins in various apoptotic models and present a new mechanism for the anti-apoptotic effects of survivin in cancer cells.
Ceballos-Cancino
G
G
Molecular Biology Laboratory, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Tlalpan, Mexico City, Mexico.
Espinosa
M
M
Maldonado
V
V
Melendez-Zajgla
J
J
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000502:physiology; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000502:physiology*; D019311:Staurosporine / Q000494:pharmacology; D000077022:Survivin
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C107489:BIRC5 protein, human; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D005047:Etoposide; D045304:Cytochromes c; D020169:Caspases; D019311:Staurosporine