PMID- 24516159
OWN - NLM
STAT- MEDLINE
DCOM- 20140422
LR  - 20220409
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 111
IP  - 8
DP  - 2014 Feb 25
TI  - HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the 
      NRF2 response.
PG  - 3032-7
LID - 10.1073/pnas.1314421111 [doi]
AB  - Oxidative stress plays a key role in late onset diseases including cancer and 
      neurodegenerative diseases such as Huntington disease. Therefore, uncovering 
      regulators of the antioxidant stress responses is important for understanding the 
      course of these diseases. Indeed, the nuclear factor erythroid 2-related factor 2 
      (NRF2), a master regulator of the cellular antioxidative stress response, is 
      deregulated in both cancer and neurodegeneration. Similar to NRF2, the tumor 
      suppressor Homologous to the E6-AP Carboxyl Terminus (HECT) domain and Ankyrin 
      repeat containing E3 ubiquitin-protein ligase 1 (HACE1) plays a protective role 
      against stress-induced tumorigenesis in mice, but its roles in the antioxidative 
      stress response or its involvement in neurodegeneration have not been 
      investigated. To this end we examined Hace1 WT and KO mice and found that Hace1 
      KO animals exhibited increased oxidative stress in brain and that the 
      antioxidative stress response was impaired. Moreover, HACE1 was found to be 
      essential for optimal NRF2 activation in cells challenged with oxidative stress, 
      as HACE1 depletion resulted in reduced NRF2 activity, stability, and protein 
      synthesis, leading to lower tolerance against oxidative stress triggers. 
      Strikingly, we found a reduction of HACE1 levels in the striatum of Huntington 
      disease patients, implicating HACE1 in the pathology of Huntington disease. 
      Moreover, ectopic expression of HACE1 in striatal neuronal progenitor cells 
      provided protection against mutant Huntingtin-induced redox imbalance and 
      hypersensitivity to oxidative stress, by augmenting NRF2 functions. These 
      findings reveal that the tumor suppressor HACE1 plays a role in the NRF2 
      antioxidative stress response pathway and in neurodegeneration.
FAU - Rotblat, Barak
AU  - Rotblat B
AD  - Department of Molecular Oncology, British Columbia Cancer Research Centre, 
      Vancouver, BC, Canada V5Z 1L3.
FAU - Southwell, Amber L
AU  - Southwell AL
FAU - Ehrnhoefer, Dagmar E
AU  - Ehrnhoefer DE
FAU - Skotte, Niels H
AU  - Skotte NH
FAU - Metzler, Martina
AU  - Metzler M
FAU - Franciosi, Sonia
AU  - Franciosi S
FAU - Leprivier, Gabriel
AU  - Leprivier G
FAU - Somasekharan, Syam Prakash
AU  - Somasekharan SP
FAU - Barokas, Adi
AU  - Barokas A
FAU - Deng, Yu
AU  - Deng Y
FAU - Tang, Tiffany
AU  - Tang T
FAU - Mathers, Joan
AU  - Mathers J
FAU - Cetinbas, Naniye
AU  - Cetinbas N
FAU - Daugaard, Mads
AU  - Daugaard M
FAU - Kwok, Brian
AU  - Kwok B
FAU - Li, Liheng
AU  - Li L
FAU - Carnie, Christopher J
AU  - Carnie CJ
FAU - Fink, Dieter
AU  - Fink D
FAU - Nitsch, Roberto
AU  - Nitsch R
FAU - Galpin, Jason D
AU  - Galpin JD
FAU - Ahern, Christopher A
AU  - Ahern CA
FAU - Melino, Gerry
AU  - Melino G
FAU - Penninger, Josef M
AU  - Penninger JM
FAU - Hayden, Michael R
AU  - Hayden MR
FAU - Sorensen, Poul H
AU  - Sorensen PH
LA  - eng
GR  - MC_U132670600/MRC_/Medical Research Council/United Kingdom
GR  - MOP-123416/CAPMC/CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140210
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (DNA Primers)
RN  - 0 (HTT protein, human)
RN  - 0 (Huntingtin Protein)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 2.3.2.26 (HACE1 protein, human)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Cell Fractionation
MH  - Corpus Striatum/metabolism
MH  - DNA Primers/genetics
MH  - Fluorescent Antibody Technique
MH  - HEK293 Cells
MH  - Humans
MH  - Huntingtin Protein
MH  - Huntington Disease/*metabolism
MH  - Mice
MH  - NF-E2-Related Factor 2/*metabolism
MH  - Nerve Tissue Proteins/metabolism
MH  - Oxidative Stress/*physiology
MH  - Reactive Oxygen Species/metabolism
MH  - Real-Time Polymerase Chain Reaction
MH  - Ubiquitin-Protein Ligases/*metabolism
PMC - PMC3939919
OTO - NOTNLM
OT  - ROS
OT  - aging
OT  - glutathione
OT  - transcription factor
COIS- The authors declare no conflict of interest.
EDAT- 2014/02/12 06:00
MHDA- 2014/04/23 06:00
PMCR- 2014/02/10
CRDT- 2014/02/12 06:00
PHST- 2014/02/12 06:00 [entrez]
PHST- 2014/02/12 06:00 [pubmed]
PHST- 2014/04/23 06:00 [medline]
PHST- 2014/02/10 00:00 [pmc-release]
AID - 1314421111 [pii]
AID - 201314421 [pii]
AID - 10.1073/pnas.1314421111 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2014 Feb 25;111(8):3032-7. doi: 
      10.1073/pnas.1314421111. Epub 2014 Feb 10.