title: Regulation of mitochondrial Smac/DIABLO-selective release by survivin.
abstract: 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.
authors.affiliation: Molecular Biology Laboratory, Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Tlalpan, Mexico City, Mexico.
authors.forename: G
authors.initials: G
authors.lastname: Ceballos-Cancino
authors.forename: M
authors.initials: M
authors.lastname: Espinosa
authors.forename: V
authors.initials: V
authors.lastname: Maldonado
authors.forename: J
authors.initials: J
authors.lastname: Melendez-Zajgla
mesh_terms: 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
chemical_list: 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