Fas-induced apoptosis in mouse hepatocytes is dependent on C/EBPbeta.
Apoptotic cell death in the liver in response to activation of the Fas pathway has been implicated in human disease states as well as liver remodeling and tissue repair. C/EBPbeta, a member of the CCAAT enhancer binding protein family of bZIP transcription factors has been linked to both growth response and apoptotic targets in the liver, and, therefore, is a likely candidate for the regulation of apoptotic liver injury. We investigated differences in apoptotic cell death in the livers of C/EBPbeta-null mice using the Jo-2 agonistic anti-Fas antibody. Apoptotic injury was dramatically reduced in C/EBPbeta -/- livers as shown by a nearly 20-fold reduction in apoptotic hepatocytes 6 hours post-Jo-2 treatment in C/EBPbeta -/- hepatocytes compared with controls (P < .04) and reduced activation of caspase 3. Bid cleavage occurred in Jo-2 treated C/EBPbeta -/- livers indicating a block of Fas-induced injury distal to the death-inducing signaling complex. The level of the antiapoptotic protein bcl-x(L) was increased greater than tenfold in the mutant animals (P < .04), which can, at least in part, account for the protection from Fas-mediated apoptosis. In contrast, bcl-x(L) mRNA levels were unchanged. These observations link C/EBPbeta to Fas-induced hepatocyte apoptosis through a mechanism that likely involves translational or posttranslational regulation of bcl-x(L).
Mukherjee
D
D
Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-6144, USA.
Kaestner
K H
KH
Kovalovich
K K
KK
Greenbaum
L E
LE
D000818:Animals; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis / Q000502:physiology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004351:Drug Resistance; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D007267:Injections; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051020:bcl-X Protein; D019014:fas Receptor / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*
D000906:Antibodies; C494812:Bcl2l1 protein, mouse; D022782:CCAAT-Enhancer-Binding Protein-beta; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051020:bcl-X Protein; D019014:fas Receptor; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases