Prostate apoptosis response gene-4 sensitizes neoplastic lymphocytes to CD95-induced apoptosis.
Evaluating the functional consequences of prostate apoptosis response gene-4 (par-4) expression in CD95-induced apoptosis of neoplastic lymphocytes, we demonstrate that par-4 increases apoptosis by upregulating the CD95 receptor on the cell surface and--with a concomitant decrease of the FLICE-like inhibitory protein (FLIP)--by promoting cleavage of the initiator caspases-8 and -10. This results in an enforced activation of the executioner caspases-6, -7, and -3 as well as in an activation of the mitochondrial pathway. Upon inhibition of caspase-8, overexpression of par-4 enables Jurkat cells to maintain a higher sensitivity to CD95-induced apoptosis by downregulating cIAP-2 and XIAP and by enforcing activation of the initiator caspase-10 as well as of the executioner caspases-6, -7, and -3.
Department of Medicine III, Johann Wolfgang Goethe-University Hospital, Theodor-Stern-Kai-7, 60590, Frankfurt am Main, Germany.
Marion
M
Bergmann
Natasa
N
Kukoc-Zivojnov
Kai U
KU
Chow
Bettina
B
Trepohl
Dieter
D
Hoelzer
Eckhart
E
Weidmann
Paris S
PS
Mitrou
Simone
S
Boehrer
D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D053222:Fas Ligand Protein; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D008214:Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000378:metabolism; D011467:Prostate / Q000201:enzymology / Q000473:pathology*; D019014:fas Receptor / Q000378:metabolism / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D019014:fas Receptor; C101296:prostate apoptosis response-4 protein