TRAF2 Exerts Its Antiapoptotic Effect by Regulating the Expression of Krüppel-Like Factor LKLF

Abstract

Tumor necrosis factor receptor (TNFR)-associated factor 2 (TRAF2) is one of the key factors that mediate TNF signaling. The deletion of TRAF2 renders cells more sensitive to TNF-induced apoptosis. Although TRAF2 is known to be required for TNF-induced JNK and NF-κB activation, the underlying mechanism of the increased sensitivity of TRAF2 null cells (TRAF2^−/−) to TNF-induced apoptosis is not fully understood. To study the underlying mechanism, we examined the difference in gene expression between TRAF2^−/− and wild-type fibroblast cells by using microarray technology. We found that one of the genes whose expression was dramatically decreased in TRAF2^−/− cells was the lung Krüppel-like factor (LKLF). Our results indicate that the expression of LKLF requires TRAF2 but is independent of TNF signaling. Although it appears that TRAF2 regulates the expression of the LKLF gene at the transcription level, TRAF2 does not function as a transcription factor itself. Our results suggest that TRAF2 regulates LKLF expression through the mitogen-activated protein kinase p38 pathway. More importantly, ectopic expression of LKLF in TRAF2^−/− cells protected cells against TNF-induced apoptosis. These results reveal a novel aspect of TRAF2 function: by regulating the expression of genes, such as LKLF, TRAF2 controls cell sensitivity to apoptosis.

ACKNOWLEDGMENTS

We thank W. C. Yeh and T. W. Mak for the TRAF2^−/− fibroblasts, M. Karin for the p38^−/− fibroblasts, J. M. Leiden and C.-N Ting for the LKLF antibody, J. Han for the MKK6AA construct, and D. LeRoith for the pBPV-hIGFIR plasmid.