PMID- 22158615
OWN - NLM
STAT- MEDLINE
DCOM- 20120322
LR  - 20211021
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 287
IP  - 5
DP  - 2012 Jan 27
TI  - Death receptors 4 and 5 activate Nox1 NADPH oxidase through riboflavin kinase to 
      induce reactive oxygen species-mediated apoptotic cell death.
PG  - 3313-25
LID - 10.1074/jbc.M111.309021 [doi]
AB  - Stimulation of the proapoptotic tumor necrosis factor (TNF)-related 
      apoptosis-inducing ligand (TRAIL) receptors, death receptors 4 (DR4) and 5 (DR5), 
      conventionally induces caspase-dependent apoptosis in tumor cells. Here we report 
      that stimulation of DR4 and/or DR5 by the agonistic protein KD548-Fc, an Fc-fused 
      DR4/DR5 dual-specific Kringle domain variant, activates plasma 
      membrane-associated Nox1 NADPH oxidase to generate superoxide anion and 
      subsequently accumulates intracellular reactive oxygen species (ROS), leading to 
      sustained c-Jun N-terminal kinase activation and eventual apoptotic cell death in 
      human HeLa and Jurkat tumor cells. KD548-Fc treatment induces the formation of a 
      DR4/DR5 signaling complex containing riboflavin kinase (RFK), Nox1, the Nox1 
      subunits (Rac1, Noxo1, and Noxa1), TNF receptor-associated death domain (TRADD), 
      and TNF receptor-associated factor 2 (TRAF2). Depletion of RFK, but not the Nox1 
      subunits, TRADD and TRAF2, failed to recruit Nox1 and Rac1 to DR4 and DR5, 
      demonstrating that RFK plays an essential role in linking DR4/DR5 with Nox1. 
      Knockdown studies also reveal that RFK, TRADD, and TRAF2 play critical, 
      intermediate, and negligible roles, respectively, in the KD548-Fc-mediated ROS 
      accumulation and downstream signaling. Binding assays using recombinantly 
      expressed proteins suggest that DR4/DR5 directly interact with cytosolic RFK 
      through RFK-binding regions within the intracellular death domains, and TRADD 
      stabilizes the DR4/DR5-RFK complex. Our results suggest that DR4 and DR5 have a 
      capability to activate Nox1 by recruiting RFK, resulting in ROS-mediated 
      apoptotic cell death in tumor cells.
FAU - Park, Kyung-Jin
AU  - Park KJ
AD  - Department of Molecular Science and Technology, Ajou University, Suwon 443-749, 
      Korea.
FAU - Lee, Chang-Han
AU  - Lee CH
FAU - Kim, Aeyung
AU  - Kim A
FAU - Jeong, Ki Jun
AU  - Jeong KJ
FAU - Kim, Chul-Ho
AU  - Kim CH
FAU - Kim, Yong-Sung
AU  - Kim YS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111209
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (RAC1 protein, human)
RN  - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (TNF Receptor-Associated Death Domain Protein)
RN  - 0 (TNF Receptor-Associated Factor 2)
RN  - 0 (TNFRSF10A protein, human)
RN  - 11062-77-4 (Superoxides)
RN  - EC 1.6.3.- (NADPH Oxidase 1)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 1.6.3.- (NOX1 protein, human)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.26 (riboflavin kinase)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 3.6.5.2 (rac1 GTP-Binding Protein)
SB  - IM
MH  - Apoptosis/*physiology
MH  - Gene Knockdown Techniques
MH  - HeLa Cells
MH  - Humans
MH  - JNK Mitogen-Activated Protein Kinases/genetics/metabolism
MH  - NADPH Oxidase 1
MH  - NADPH Oxidases/genetics/*metabolism
MH  - Phosphotransferases (Alcohol Group Acceptor)/genetics/*metabolism
MH  - Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics/*metabolism
MH  - Superoxides/*metabolism
MH  - TNF Receptor-Associated Death Domain Protein/genetics/metabolism
MH  - TNF Receptor-Associated Factor 2/genetics/metabolism
MH  - rac1 GTP-Binding Protein/genetics/metabolism
PMC - PMC3270986
EDAT- 2011/12/14 06:00
MHDA- 2012/03/23 06:00
PMCR- 2013/01/27
CRDT- 2011/12/14 06:00
PHST- 2011/12/14 06:00 [entrez]
PHST- 2011/12/14 06:00 [pubmed]
PHST- 2012/03/23 06:00 [medline]
PHST- 2013/01/27 00:00 [pmc-release]
AID - S0021-9258(20)48283-3 [pii]
AID - M111.309021 [pii]
AID - 10.1074/jbc.M111.309021 [doi]
PST - ppublish
SO  - J Biol Chem. 2012 Jan 27;287(5):3313-25. doi: 10.1074/jbc.M111.309021. Epub 2011 
      Dec 9.