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 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.
Hur
Gang Min
GM
Cell and Cancer Biology Branch, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Kim
You-Sun
YS
Won
Minho
M
Choksi
Swati
S
Liu
Zheng-gang
ZG
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004249:DNA Damage; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D015398:Signal Transduction; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*
D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; D048055:Mitogen-Activated Protein Kinase 8; D048670:MAP Kinase Kinase 4