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Induction of TNF-sensitive cellular phenotype by c-Myc involves p53 and impaired NF-kappaB activation
J Klefstrom1, E Arighi, T Littlewood
1Molecular/Cancer Biology Laboratory, Haartman Institute, PO Box 21, 00014 University of Helsinki, Finland.
The EMBO Journal
|February 21, 1998
Summary
Deregulation of c-Myc makes normal cells sensitive to tumor necrosis factor (TNF)-induced death. This involves impaired cell survival signaling and p53, highlighting a new mechanism for cancer therapy.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Normal fibroblasts resist tumor necrosis factor (TNF)-induced cell death.
- Oncoproteins, such as c-Myc, can alter cellular responses to TNF.
- Understanding how oncoproteins modulate TNF signaling is crucial for cancer research.
Purpose of the Study:
- To investigate how deregulated c-Myc affects TNF-induced signaling pathways.
- To determine the role of c-Myc in TNF-mediated cytotoxicity.
- To elucidate the involvement of p53 in c-Myc and TNF-induced apoptosis.
Main Methods:
- Utilized fibroblasts with conditionally active c-Myc.
- Analyzed TNF-elicited signaling responses, including phospholipase A2, JNK, and NF-kappaB activation.
- Assessed apoptosis in wild-type and p53-deficient fibroblasts.
Main Results:
- c-Myc impaired TNF-induced activation of survival pathways (PLA2, JNK, NF-kappaB).
- Overexpression of NF-kappaB p65 inhibited TNF-induced cell death in c-Myc expressing cells.
- TNF and c-Myc induced apoptosis, dependent on p53, but not its transcriptional activity.
Conclusions:
- Cytotoxic TNF activity in oncoprotein-expressing cells involves p53.
- Impaired cell survival signaling contributes to TNF-induced cell death in the presence of c-Myc.
- Targeting these pathways could offer novel therapeutic strategies for cancers with c-Myc deregulation.
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