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KMID : 0811720080120040185
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Korean Journal of Physiology & Pharmacology
2008 Volume.12 No. 4 p.185 ~ p.192
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Long-term Activation of c-Jun N-terminal Kinase through Receptor Interacting Protein is Associated with DNA Damage-induced Cell Death
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Seok Jeong-Ho
Shin Sang-Hee
Won Min-Ho
Park Jong-Sun
Hur Gang-Min
Hong Jang-Hee
Byun Hee-Sun
Park Kyeong-Ah
Kim Young-Rae
Choi Byung-Lyul
Lee Hyun-Ji
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Abstract
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Activation of c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase family, is an important cellular response that modulates the outcome of the cells which are exposed to the tumor necrosis factor (TNF) or the genotoxic stress including DNA damaging agents. Although it is known that JNK is activated in response to genotoxic stress, neither the pathways to transduce signals to activate JNK nor the primary sensors of the cells that trigger the stress response have been identified. Here, we report that the receptor interacting protein (RIP), a key adaptor protein of TNF signaling, was required to activate JNK in the cells treated with certain DNA damaging agents such as adriamycin (Adr) and 1-?-D-arabinofuranosylcytosine (Ara-C) that cause slow and sustained activation, but it was not required when treated with N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and short wavelength UV, which causes quick and transient activation. Our findings revealed that this sustained JNK activation was not mediated by the TNF (tumor necrosis factor) receptor signaling, but it required a functional ATM (ataxia telangiectasia) activity. In addition, JNK inhibitor SP-600125 significantly blocked the Adr-induced cell death, but it did not affect the cell death induced by MNNG. These findings suggest that the sustained activation of JNK mediated by RIP plays an important role in the DNA damage-induced cell death, and that the duration of JNK activation relays a different stress response to determine the cell fate.
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KEYWORD
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DNA damage, Cell death, Receptor interacting protein, c-Jun N-terminal kinase, Poly (ADP- ribose) polymerase
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