C/EBPβ regulates TNF induced MnSOD expression and protection against apoptosis

The CCAAT enhancer binding protein-beta (C/EBP beta) is a critical regulator of many cellular processes. Exposure of C/EBP beta-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-kappa B was normal in C/EBP beta-deficient cells, induction of manganous superoxide dismutase (MnSOD) gene did not occur. Ectopic expression of C/EBP beta in C/EBP beta-deficient fibroblasts prevented TNF-induced apoptosis. C/EBP beta complemented cells were able to induce MnSOD in response to TNF, ruling out the possibilities that C/EBP beta could render protection by regulating early apoptotic gene expression and/or NF-kappa B p65 expression. Moreover, C/EBP beta-deficient cells stably transfected with an MnSOD expression vector bypassed the requirement of C/EBP beta in protection against TNF-induced cell death, suggesting that C/EBP beta protects TNF-induced apoptotic cell death through its role in activating MnSOD expression. Mechanistically, C/EBP beta was required for induced NF-kappa B 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/EBP beta in MnSOD regulation through remodeling of local chromatin structure.