C/EBPbeta regulates TNF induced MnSOD expression and protection against apoptosis.
The CCAAT enhancer binding protein-beta (C/EBPbeta) is a critical regulator of many cellular processes. Exposure of C/EBPbeta-deficient fibroblasts to tumor necrosis factor-alpha (TNF) resulted in their death due to apoptosis. While, the expression of Bad, Bcl-2, Bcl-x, CAS, and hILP/XIAP, as well as the nuclear translocation of NF-kappaB was normal in C/EBPbeta-deficient cells, induction of manganous superoxide dismutase (MnSOD) gene did not occur. Ectopic expression of C/EBPbeta in C/EBPbeta-deficient fibroblasts prevented TNF-induced apoptosis. C/EBPbeta complemented cells were able to induce MnSOD in response to TNF, ruling out the possibilities that C/EBPbeta could render protection by regulating early apoptotic gene expression and/or NF-kappaB p65 expression. Moreover, C/EBPbeta-deficient cells stably transfected with an MnSOD expression vector bypassed the requirement of C/EBPbeta in protection against TNF-induced cell death, suggesting that C/EBPbeta protects TNF-induced apoptotic cell death through its role in activating MnSOD expression. Mechanistically, C/EBPbeta was required for induced NF-kappaB p65 binding to MnSOD's intronic TNF response element and indispensable for histone acetylation of the element in response to TNF. These results suggest a role for C/EBPbeta in MnSOD regulation through remodeling of local chromatin structure.
Ranjan
Priya
P
Department of Microbiology and Immunology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322, USA.
Boss
Jeremy M
JM
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly / Q000502:physiology; D019610:Cytoprotection / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000502:physiology; D051548:Histone Acetyltransferases / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D021381:Protein Transport / Q000502:physiology; D050436:Regulatory Elements, Transcriptional / Q000502:physiology; D013482:Superoxide Dismutase / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000633:toxicity
D051017:Apoptosis Regulatory Proteins; D022782:CCAAT-Enhancer-Binding Protein-beta; D004268:DNA-Binding Proteins; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D013482:Superoxide Dismutase; D051548:Histone Acetyltransferases