PMID- 27387771
OWN - NLM
STAT- MEDLINE
DCOM- 20180104
LR  - 20180122
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Linking)
VI  - 97
DP  - 2016 Aug
TI  - Intracellular labile iron determines H2O2-induced apoptotic signaling via 
      sustained activation of ASK1/JNK-p38 axis.
PG  - 454-465
LID - S0891-5849(16)30322-7 [pii]
LID - 10.1016/j.freeradbiomed.2016.07.002 [doi]
AB  - Hydrogen peroxide (H2O2) acts as a second messenger in signal transduction 
      participating in several redox regulated pathways, including cytokine and growth 
      factor stimulated signals. However, the exact molecular mechanisms underlying 
      these processes remain poorly understood and require further investigation. In 
      this work, using Jurkat T lymphoma cells and primary human umbilical vein 
      endothelial cells, it was observed that changes in intracellular "labile iron" 
      were able to modulate signal transduction in H2O2-induced apoptosis. Chelation of 
      intracellular labile iron by desferrioxamine rendered cells resistant to 
      H2O2-induced apoptosis. In order to identify the exact points of iron action, we 
      investigated selected steps in H2O2-mediated apoptotic pathway, focusing on 
      mitogen activated protein kinases (MAPKs) JNK, p38 and ERK. It was observed that 
      spatiotemporal changes in intracellular labile iron, induced by H2O2, influenced 
      the oxidation pattern of the upstream MAP3K ASK1 and promoted the sustained 
      activation of JNK-p38 axis in a defined time-dependent context. Moreover, we 
      indicate that H2O2 induced spatiotemporal changes in intracellular labile iron, 
      at least in part, by triggering the destabilization of lysosomal compartments, 
      promoting a concomitant early response in proteins of iron homeostasis. These 
      results raise the possibility that iron-mediated oxidation of distinct proteins 
      may be implicated in redox signaling processes. Since labile iron can be 
      pharmacologically modified in vivo, it may represent a promising target for 
      therapeutic interventions in related pathological conditions.
CI  - Copyright (c) 2016 Elsevier Inc. All rights reserved.
FAU - Mantzaris, M D
AU  - Mantzaris MD
AD  - Laboratory of Biological Chemistry, School of Health Sciences, Faculty of 
      Medicine, University of Ioannina, Greece.
FAU - Bellou, S
AU  - Bellou S
AD  - Foundation for Research & Technology-Hellas, Institute of Molecular Biology & 
      Biotechnology, Department of Biomedical Research, Ioannina, Greece.
FAU - Skiada, V
AU  - Skiada V
AD  - Laboratory of Biological Chemistry, School of Health Sciences, Faculty of 
      Medicine, University of Ioannina, Greece.
FAU - Kitsati, N
AU  - Kitsati N
AD  - Laboratory of Biological Chemistry, School of Health Sciences, Faculty of 
      Medicine, University of Ioannina, Greece.
FAU - Fotsis, T
AU  - Fotsis T
AD  - Laboratory of Biological Chemistry, School of Health Sciences, Faculty of 
      Medicine, University of Ioannina, Greece; Foundation for Research & 
      Technology-Hellas, Institute of Molecular Biology & Biotechnology, Department of 
      Biomedical Research, Ioannina, Greece.
FAU - Galaris, D
AU  - Galaris D
AD  - Laboratory of Biological Chemistry, School of Health Sciences, Faculty of 
      Medicine, University of Ioannina, Greece. Electronic address: dgalaris@uoi.gr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160705
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - E1UOL152H7 (Iron)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinase 5)
RN  - EC 2.7.11.25 (MAP3K5 protein, human)
RN  - EC 3.1.3.48 (DUSP1 protein, human)
RN  - EC 3.1.3.48 (Dual Specificity Phosphatase 1)
SB  - IM
MH  - *Apoptosis
MH  - Dual Specificity Phosphatase 1/metabolism
MH  - Human Umbilical Vein Endothelial Cells/drug effects/metabolism
MH  - Humans
MH  - Hydrogen Peroxide/*metabolism
MH  - Iron/*metabolism
MH  - JNK Mitogen-Activated Protein Kinases/metabolism
MH  - Jurkat Cells
MH  - Lysosomes/metabolism
MH  - MAP Kinase Kinase Kinase 5/metabolism
MH  - *MAP Kinase Signaling System
MH  - Oxidation-Reduction
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
OTO - NOTNLM
OT  - Apoptosis
OT  - Apoptosis signal-regulating kinase (ASK-1)
OT  - Hydrogen peroxide
OT  - Labile iron
OT  - Mitogen activated protein kinases (MAPKs)
OT  - Redox signaling
EDAT- 2016/07/09 06:00
MHDA- 2018/01/05 06:00
CRDT- 2016/07/09 06:00
PHST- 2016/03/31 00:00 [received]
PHST- 2016/06/15 00:00 [revised]
PHST- 2016/07/04 00:00 [accepted]
PHST- 2016/07/09 06:00 [entrez]
PHST- 2016/07/09 06:00 [pubmed]
PHST- 2018/01/05 06:00 [medline]
AID - S0891-5849(16)30322-7 [pii]
AID - 10.1016/j.freeradbiomed.2016.07.002 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2016 Aug;97:454-465. doi: 
      10.1016/j.freeradbiomed.2016.07.002. Epub 2016 Jul 5.