PMID- 21464371
OWN - NLM
STAT- MEDLINE
DCOM- 20110908
LR  - 20211020
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 117
IP  - 22
DP  - 2011 Jun 2
TI  - Induction of human fetal hemoglobin via the NRF2 antioxidant response signaling 
      pathway.
PG  - 5987-97
LID - 10.1182/blood-2010-10-314096 [doi]
AB  - Although hematopoietic stem cell transplantation and gene therapy have the 
      potential to cure beta-thalassemia and sickle cell disease, they are not currently 
      available to most people with these diseases. In the near term, pharmacologic 
      induction of fetal hemoglobin (HbF) may offer the best possibility for safe, 
      effective, and widely available therapy. In an effort to define new pathways for 
      targeted drug development for HbF induction, we evaluated the nuclear factor 
      erythroid 2-related factor 2 (NRF2) antioxidant response element signaling 
      pathway. We found that 3 well-known activators of this pathway increased gamma-globin 
      mRNA at nontoxic doses in K562 cells. Tert-butylhydroquinone (tBHQ), the most 
      active of these compounds, increased cellular levels and nuclear translocation of 
      NRF2 and binding of NRF2 to the gamma-globin promoter. siRNA knockdown of NRF2 
      inhibited gamma-globin induction by tBHQ. When tested in human primary erythroid 
      cells, tBHQ induced NRF2 binding to the gamma-globin promoter, increased gamma-globin 
      mRNA and HbF, and suppressed beta-globin mRNA and HbA, resulting in a > 3-fold 
      increase in the percentage of HbF. These results suggest that drugs that activate 
      the NRF2/antioxidant response element signaling pathway have the potential to 
      induce therapeutic levels of HbF in people with beta-hemoglobinopathies.
FAU - Macari, Elizabeth R
AU  - Macari ER
AD  - Department of Pharmacology & Toxicology.
FAU - Lowrey, Christopher H
AU  - Lowrey CH
LA  - eng
GR  - R01 HL073442/HL/NHLBI NIH HHS/United States
GR  - T32 CA009658/CA/NCI NIH HHS/United States
GR  - HL73442/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110404
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antioxidants)
RN  - 0 (Hydroquinones)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (beta-Globins)
RN  - 0 (gamma-Globins)
RN  - 9034-63-3 (Fetal Hemoglobin)
RN  - C12674942B (2-tert-butylhydroquinone)
RN  - EC 1.13.12.- (Luciferases)
SB  - IM
MH  - Antioxidants/*therapeutic use
MH  - Blotting, Western
MH  - Cell Differentiation
MH  - Chromatin Immunoprecipitation
MH  - Electrophoretic Mobility Shift Assay
MH  - Erythroid Cells/metabolism
MH  - Fetal Hemoglobin/*metabolism
MH  - Humans
MH  - Hydroquinones/*therapeutic use
MH  - K562 Cells
MH  - Luciferases/metabolism
MH  - NF-E2-Related Factor 2/antagonists & inhibitors/genetics/*metabolism
MH  - Promoter Regions, Genetic
MH  - Protein Transport
MH  - RNA, Messenger/genetics
MH  - RNA, Small Interfering/genetics
MH  - Response Elements
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/*drug effects
MH  - beta-Globins
MH  - beta-Thalassemia/metabolism/pathology/*prevention & control
MH  - gamma-Globins/*genetics/metabolism
PMC - PMC3112042
EDAT- 2011/04/06 06:00
MHDA- 2011/09/09 06:00
PMCR- 2012/06/02
CRDT- 2011/04/06 06:00
PHST- 2011/04/06 06:00 [entrez]
PHST- 2011/04/06 06:00 [pubmed]
PHST- 2011/09/09 06:00 [medline]
PHST- 2012/06/02 00:00 [pmc-release]
AID - S0006-4971(20)45012-8 [pii]
AID - 2010/314096 [pii]
AID - 10.1182/blood-2010-10-314096 [doi]
PST - ppublish
SO  - Blood. 2011 Jun 2;117(22):5987-97. doi: 10.1182/blood-2010-10-314096. Epub 2011 
      Apr 4.