PMID- 25492865
OWN - NLM
STAT- MEDLINE
DCOM- 20150415
LR  - 20220310
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 290
IP  - 5
DP  - 2015 Jan 30
TI  - Apurinic/apyrimidinic endonuclease/redox factor-1 (APE1/Ref-1) redox function 
      negatively regulates NRF2.
PG  - 3057-68
LID - 10.1074/jbc.M114.621995 [doi]
AB  - Apurinic/apyrimidinic endonuclease/redox factor-1 (APE1/Ref-1) (henceforth 
      referred to as Ref-1) is a multifunctional protein that in addition to its base 
      excision DNA repair activity exerts redox control of multiple transcription 
      factors, including nuclear factor kappa-light chain enhancer of activated B cells 
      (NF-kappaB), STAT3, activator protein-1 (AP-1), hypoxia-inducible factor-1 (HIF-1), 
      and tumor protein 53 (p53). In recent years, Ref-1 has emerged as a promising 
      therapeutic target in cancer, particularly in pancreatic ductal carcinoma. 
      Although a significant amount of research has centered on Ref-1, no wide-ranging 
      approach had been performed on the effects of Ref-1 inhibition and transcription 
      factor activity perturbation. Starting with a broader approach, we identified a 
      previously unsuspected effect on the nuclear factor erythroid-related factor 2 
      (NRF2), a critical regulator of cellular defenses against oxidative stress. Based 
      on genetic and small molecule inhibitor-based methodologies, we demonstrated that 
      repression of Ref-1 potently activates NRF2 and its downstream targets in a 
      dose-dependent fashion, and that the redox, rather than the DNA repair function 
      of Ref-1 is critical for this effect. Intriguingly, our results also indicate 
      that this pathway does not involve reactive oxygen species. The link between 
      Ref-1 and NRF2 appears to be present in all cells tested in vitro, noncancerous 
      and cancerous, including patient-derived tumor samples. In particular, we focused 
      on understanding the implications of the novel interaction between these two 
      pathways in primary pancreatic ductal adenocarcinoma tumor cells and provide the 
      first evidence that this mechanism has implications for overcoming the resistance 
      against experimental drugs targeting Ref-1 activity, with clear translational 
      implications.
CI  - (c) 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Fishel, Melissa L
AU  - Fishel ML
AD  - From the Departments of Pediatrics, Wells Center for Pediatric Research, 
      Pharmacology and Toxicology, mfishel@iu.edu.
FAU - Wu, Xue
AU  - Wu X
AD  - Microbiology and Immunology.
FAU - Devlin, Cecilia M
AU  - Devlin CM
AD  - Medicine.
FAU - Logsdon, Derek P
AU  - Logsdon DP
AD  - Pharmacology and Toxicology.
FAU - Jiang, Yanlin
AU  - Jiang Y
AD  - From the Departments of Pediatrics, Wells Center for Pediatric Research.
FAU - Luo, Meihua
AU  - Luo M
AD  - From the Departments of Pediatrics, Wells Center for Pediatric Research, 
      Pharmacology and Toxicology.
FAU - He, Ying
AU  - He Y
AD  - From the Departments of Pediatrics, Wells Center for Pediatric Research.
FAU - Yu, Zhangsheng
AU  - Yu Z
AD  - Biostatistics, and.
FAU - Tong, Yan
AU  - Tong Y
AD  - Biostatistics, and.
FAU - Lipking, Kelsey P
AU  - Lipking KP
AD  - Pathology, Indiana University School of Medicine, Indianapolis, Indiana 46202 
      and.
FAU - Maitra, Anirban
AU  - Maitra A
AD  - the Departments of Oncology and Pathology, Johns Hopkins University School of 
      Medicine, Baltimore, Maryland 21205.
FAU - Rajeshkumar, N V
AU  - Rajeshkumar NV
AD  - the Departments of Oncology and Pathology, Johns Hopkins University School of 
      Medicine, Baltimore, Maryland 21205.
FAU - Scandura, Glenda
AU  - Scandura G
AD  - Medicine.
FAU - Kelley, Mark R
AU  - Kelley MR
AD  - From the Departments of Pediatrics, Wells Center for Pediatric Research, 
      Pharmacology and Toxicology.
FAU - Ivan, Mircea
AU  - Ivan M
AD  - Microbiology and Immunology, Medicine, mivan@iu.edu.
LA  - eng
GR  - CA121168/CA/NCI NIH HHS/United States
GR  - 1R01 CA155332-01/CA/NCI NIH HHS/United States
GR  - CA121168S1/CA/NCI NIH HHS/United States
GR  - CA167291/CA/NCI NIH HHS/United States
GR  - R01 CA121168/CA/NCI NIH HHS/United States
GR  - R01 CA167291/CA/NCI NIH HHS/United States
GR  - R01 CA155332/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20141209
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 4.2.99.18 (APEX1 protein, human)
RN  - EC 4.2.99.18 (DNA-(Apurinic or Apyrimidinic Site) Lyase)
SB  - IM
MH  - Cell Line, Tumor
MH  - DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics/*metabolism
MH  - Humans
MH  - NF-E2-Related Factor 2/genetics/*metabolism
MH  - Oxidation-Reduction
MH  - Pancreatic Neoplasms/genetics/*metabolism
MH  - Reactive Oxygen Species/metabolism
PMC - PMC4317024
OTO - NOTNLM
OT  - APE1/Ref-1
OT  - HMOX1
OT  - Hypoxia
OT  - Nuclear Factor 2 (Erythroid-derived 2-like Factor) (NFE2L2) (Nrf2)
OT  - Pancreatic Adenocarcinoma
OT  - Reactive Oxygen Species (ROS)
OT  - Redox Signaling
OT  - Transcription Factor
EDAT- 2014/12/11 06:00
MHDA- 2015/04/16 06:00
PMCR- 2016/01/30
CRDT- 2014/12/11 06:00
PHST- 2014/12/11 06:00 [entrez]
PHST- 2014/12/11 06:00 [pubmed]
PHST- 2015/04/16 06:00 [medline]
PHST- 2016/01/30 00:00 [pmc-release]
AID - S0021-9258(20)49273-7 [pii]
AID - M114.621995 [pii]
AID - 10.1074/jbc.M114.621995 [doi]
PST - ppublish
SO  - J Biol Chem. 2015 Jan 30;290(5):3057-68. doi: 10.1074/jbc.M114.621995. Epub 2014 
      Dec 9.