Related Experiment Videos
TRAF2 exerts its antiapoptotic effect by regulating the expression of Krüppel-like factor LKLF
Yong Lin1, Jennifer Ryan, Joseph Lewis
1Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
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-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.
Insights
Tumor necrosis factor receptor-associated factor 2 (TRAF2) regulates lung Krüppel-like factor (LKLF) expression, controlling apoptosis sensitivity. Restoring LKLF protects TRAF2-deficient cells from TNF-induced cell death.
Area of Science:
- Cellular biology
- Molecular mechanisms of apoptosis
- Signal transduction pathways
Background:
- Tumor necrosis factor receptor (TNFR)-associated factor 2 (TRAF2) is crucial for TNF signaling.
- TRAF2 deficiency increases cellular sensitivity to TNF-induced apoptosis.
- The precise mechanisms underlying this heightened sensitivity remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms behind TRAF2-mediated regulation of apoptosis sensitivity.
- To identify genes regulated by TRAF2 that influence TNF-induced apoptosis.
- To investigate the role of TRAF2 in gene expression changes in response to TNF signaling.
Main Methods:
- Gene expression profiling using microarray technology comparing TRAF2(-/-) and wild-type fibroblasts.
- Analysis of LKLF expression levels in TRAF2-deficient cells.
- Investigation of TRAF2's role in LKLF transcription and its regulation via the p38 MAPK pathway.
- Assessment of apoptosis sensitivity following ectopic LKLF expression in TRAF2(-/-) cells.
Main Results:
- Microarray analysis revealed significantly decreased lung Krüppel-like factor (LKLF) expression in TRAF2(-/-) cells.
- LKLF expression requires TRAF2 but is independent of TNF signaling, suggesting transcriptional regulation by TRAF2.
- TRAF2 regulates LKLF expression through the p38 mitogen-activated protein kinase (MAPK) pathway.
- Ectopic expression of LKLF conferred protection against TNF-induced apoptosis in TRAF2(-/-) cells.
Conclusions:
- TRAF2 plays a novel role in controlling apoptosis sensitivity by regulating gene expression.
- TRAF2-mediated regulation of LKLF expression is a key mechanism influencing cellular response to TNF-induced apoptosis.
- LKLF acts as a protective factor against TNF-induced apoptosis, mediated by TRAF2 signaling.