Upon drug-induced apoptosis expression of prostate-apoptosis-response-gene-4 promotes cleavage of caspase-8, bid and mitochondrial release of cytochrome c.
Par-4 functions as a tumor suppressor antagonizing the transforming capacity and the resistance of malignant cells towards apoptotic stimuli. After demonstrating that par-4 promotes apoptosis by activating signaling of the intrinsic pathway of apoptosis, we hypothesized that par-4 also impacts on key molecules of the extrinsic pathway without the requirement of a receptor/ligand interaction. Here, we provide first evidence, that expression of par-4 increases cleavage of caspase-8, truncation of Bid and its translocation to the mitochondria, resulting in an augmentation of cytochrome c and AIF efflux into the cytosol, effects par-4-positive cells are able to retain to a higher extent than par-4-negative cells upon inhibition of caspase-3 activation.
Boehrer
Simone
S
Department of Medicine III, Johann Wolfgang Goethe-University Hospital, Frankfurt, Germany. SBoehrer@gmx.de
Kukoc-Zivojnov
Natasa
N
Nowak
Daniel
D
Bergmann
Marion
M
Baum
Christine
C
Puccetti
Elena
E
Weidmann
Eckhart
E
Hoelzer
Dieter
D
Mitrou
Paris S
PS
Chow
Kai Uwe
KU
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000378:metabolism; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D008928:Mitochondria / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C101296:prostate apoptosis response-4 protein; D004317:Doxorubicin; D045304:Cytochromes c; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases