PMID- 18689799
OWN - NLM
STAT- MEDLINE
DCOM- 20090210
LR  - 20171213
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Linking)
VI  - 17
IP  - 21
DP  - 2008 Nov 1
TI  - Synergistic activation of the human MnSOD promoter by DJ-1 and PGC-1alpha: 
      regulation by SUMOylation and oxidation.
PG  - 3357-67
LID - 10.1093/hmg/ddn230 [doi]
AB  - Oxidative stress contributes to the development of neurodegenerative diseases. 
      DJ-1, a protein genetically linked to Parkinson's disease (PD), has been 
      implicated in oxidative stress defense and transcriptional regulation. However, 
      it is unclear whether these two aspects of the DJ-1 function are connected. Here, 
      we show that the inactivation of DJ-1 causes decreased expression of the human 
      MnSOD. DJ-1 stimulates the activity of a master regulator of mitochondrial 
      biogenesis and stress response, peroxisome proliferator-activated receptor-gamma 
      co-activator 1alpha (PGC-1alpha), in the transcription of the MnSOD. Although 
      DJ-1 does not interact with PGC-1alpha directly, it inhibits the SUMOylation of a 
      transcriptional repressor, pyrimidine tract-binding protein-associated splicing 
      factor (PSF). PSF binds PGC-1alpha and suppresses its transcriptional activity. 
      In contrast, a SUMOylation-deficient PSF mutant exhibits reduced binding to 
      PGC-1alpha and promotes its activity. SUMO-specific isopeptidase SENP-1 further 
      enhances the synergy between DJ-1 and PGC-1alpha, whereas an SUMO E3 ligase 
      protein inhibitor of activated STAT Y completely blocks the synergy. Conversely, 
      oxidative modification renders DJ-1 unable to inhibit SUMOylation, resulting in 
      attenuated transcriptional synergy between DJ-1 and PGC-1alpha. Therefore, our 
      results validate DJ-1 as a transcriptional regulator in mitochondrial oxidative 
      stress response and imply that the oxidation-mediated functional impairment of 
      DJ-1 leads to gradual dysregulation of the SUMO pathway. Consequent abnormal 
      mitochondrial gene expression may contribute to the development of sporadic PD.
FAU - Zhong, Nan
AU  - Zhong N
AD  - Department of Neurology, Caritas St Elizabeth's Medical Center, Tufts University 
      School of Medicine, Boston, MA 02135, USA.
FAU - Xu, Jin
AU  - Xu J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080808
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 0 (Heat-Shock Proteins)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Oncogene Proteins)
RN  - 0 (PPARGC1A protein, human)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (SUMO-1 Protein)
RN  - 0 (Transcription Factors)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - EC 3.1.2.- (PARK7 protein, human)
RN  - EC 3.1.2.- (Protein Deglycase DJ-1)
SB  - IM
MH  - ATP-Binding Cassette Transporters/metabolism
MH  - Cell Line, Tumor
MH  - *Gene Expression Regulation, Enzymologic
MH  - Heat-Shock Proteins/*metabolism
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/*metabolism
MH  - Oncogene Proteins/*metabolism
MH  - Oxidation-Reduction
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
MH  - Promoter Regions, Genetic/*genetics
MH  - Protein Deglycase DJ-1
MH  - SUMO-1 Protein/*metabolism
MH  - Superoxide Dismutase/*metabolism
MH  - Transcription Factors/*metabolism
EDAT- 2008/08/12 09:00
MHDA- 2009/02/12 09:00
CRDT- 2008/08/12 09:00
PHST- 2008/08/12 09:00 [pubmed]
PHST- 2009/02/12 09:00 [medline]
PHST- 2008/08/12 09:00 [entrez]
AID - ddn230 [pii]
AID - 10.1093/hmg/ddn230 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2008 Nov 1;17(21):3357-67. doi: 10.1093/hmg/ddn230. Epub 2008 Aug 
      8.