Negative regulation of the Apaf-1 apoptosome by Hsp70.
Release of cytochrome c from mitochondria by apoptotic signals induces ATP/dATP-dependent formation of the oligomeric Apaf-1-caspase-9 apoptosome. Here we show that the documented anti-apoptotic effect of the principal heat-shock protein, Hsp70, is mediated through its direct association with the caspase-recruitment domain (CARD) of Apaf-1 and through inhibition of apoptosome formation. The interaction between Hsp70 and Apaf-1 prevents oligomerization of Apaf-1 and association of Apaf-1 with procaspase-9. On the basis of these results, we propose that resistance to apoptosis exhibited by stressed cells and some tumours, which constitutively express high levels of Hsp70, may be due in part to modulation of Apaf-1 function by Hsp70.
Center for Apoptosis Research and Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
A
A
Saleh
S M
SM
Srinivasula
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L
Balkir
P D
PD
Robbins
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ES
Alnemri
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D015153:Blotting, Western; D053453:Caspase 9; D020169:Caspases / Q000737:chemistry / Q000378:metabolism; D002457:Cell Extracts; D002460:Cell Line; D002474:Cell-Free System; D003574:Cytochrome c Group / Q000378:metabolism; D003838:Deoxyadenine Nucleotides / Q000378:metabolism / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000737:chemistry / Q000378:metabolism; D015870:Gene Expression; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006358:Hot Temperature; D006801:Humans; D008024:Ligands; D046911:Macromolecular Substances; D011233:Precipitin Tests; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D002457:Cell Extracts; D003574:Cytochrome c Group; D003838:Deoxyadenine Nucleotides; D004792:Enzyme Precursors; D018840:HSP70 Heat-Shock Proteins; D008024:Ligands; D046911:Macromolecular Substances; D011506:Proteins; D000255:Adenosine Triphosphate; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases; C026600:2'-deoxyadenosine triphosphate