TRAF2 exerts its antiapoptotic effect by regulating the expression of Krüppel-like factor LKLF.
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-kappaB 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.
Lin
Yong
Y
Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Ryan
Jennifer
J
Lewis
Joseph
J
Wani
Maqsood A
MA
Lingrel
Jerry B
JB
Liu
Zheng-Gang
ZG
D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D016923:Cell Death; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids / Q000378:metabolism; D011506:Proteins / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases
D018076:DNA, Complementary; C096161:KLF2 protein, human; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D016328:NF-kappa B; D011506:Proteins; D047992:TNF Receptor-Associated Factor 2; D015534:Trans-Activators; D008156:Luciferases; D005982:Glutathione Transferase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases