The Death Domain Kinase RIP Has an Important Role in DNA Damage-induced, p53-independent Cell Death

Tumor suppressor p53 plays a critical role in cellular responses, such as cell cycle arrest and apoptosis following DNA damage. DNA damage-induced cell death can be mediated by a p53-dependent or p53-independent pathway. Although p53-mediated apoptosis has been well documented, little is known about...

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Bibliographic Details
Published in:The Journal of biological chemistry 2006-09, Vol.281 (35), p.25011-25017
Main Authors: Hur, Gang Min, Kim, You-Sun, Won, Minho, Choksi, Swati, Liu, Zheng-gang
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Blotting, Western
Cell Line, Tumor
DNA Damage
Fibroblasts - metabolism
Humans
MAP Kinase Kinase 4 - metabolism
Mice
Mice, Transgenic
Mitogen-Activated Protein Kinase 8 - metabolism
Mutation
Protein-Serine-Threonine Kinases - physiology
Receptor-Interacting Protein Serine-Threonine Kinases
Signal Transduction
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins - physiology
Tumor Suppressor Protein p53 - metabolism
Tumor Suppressor Protein p53 - physiology
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Summary:Tumor suppressor p53 plays a critical role in cellular responses, such as cell cycle arrest and apoptosis following DNA damage. DNA damage-induced cell death can be mediated by a p53-dependent or p53-independent pathway. Although p53-mediated apoptosis has been well documented, little is known about the signaling components of p53-independent cell death. Here we report that the death domain kinase, RIP (receptor-interacting protein), is important for DNA damage-induced, p53-independent cell death. DNA damage induces cell death in both wild-type and p53–/– mouse embryonic fibroblast cells. We found that RIP–/– mouse embryonic fibroblast cells, which have a mutant form of the p53 protein, are resistant to DNA damage-induced cell death. The reconstitution of RIP protein expression in RIP–/– cells restored the sensitivity of cells to DNA damage-induced cell death. We also found that RIP mediates this process through activating mitogen-activated protein kinase, JNK1. Furthermore, knocking down the expression of RIP blocked DNA damage-induced cell death in the human colon cancer cell line, p53 null HCT 116. Taken together, our study demonstrates that RIP is one of the critical components involved in mediating DNA damage-induced, p53-independent cell death.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M605577200