PMID- 20351112
OWN - NLM
STAT- MEDLINE
DCOM- 20100624
LR  - 20231213
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 285
IP  - 23
DP  - 2010 Jun 4
TI  - Regulation of NT-PGC-1alpha subcellular localization and function by protein 
      kinase A-dependent modulation of nuclear export by CRM1.
PG  - 18039-50
LID - 10.1074/jbc.M109.083121 [doi]
AB  - Peroxisome proliferator-activated receptor gamma co-activator-1alpha (PGC-1alpha) 
      plays a central role in the regulation of cellular energy metabolism and 
      metabolic adaptation to environmental and nutritional stimuli. We recently 
      described a novel, biologically active splice variant of PGC-1alpha 
      (NT-PGC-1alpha, amino acids 1-270) that retains the ability to interact with and 
      transactivate nuclear hormone receptors through its N-terminal transactivation 
      domain. Whereas PGC-1alpha is an unstable nuclear protein sensitive to 
      ubiquitin-mediated targeting to the proteasome, NT-PGC-1alpha is relatively 
      stable and predominantly cytoplasmic, suggesting that its ability to interact 
      with and activate nuclear receptors and transcription factors is dependent upon 
      regulated access to the nucleus. We provide evidence that NT-PGC-1alpha interacts 
      with the nuclear exportin, CRM1, through a specific leucine-rich domain (nuclear 
      export sequence) that regulates its export to the cytoplasm. The nuclear export 
      of NT-PGC-1alpha is inhibited by protein kinase A-dependent phosphorylation of 
      Ser-194, Ser-241, and Thr-256 on NT-PGC-1alpha, which effectively increases its 
      nuclear concentration. Using site-directed mutagenesis to prevent or mimic 
      phosphorylation at these sites, we show that the transcriptional activity of 
      NT-PGC-1alpha is regulated in part through regulation of its subcellular 
      localization. These findings suggest that the function of NT-PGC-1alpha as a 
      transcriptional co-activator is regulated by protein kinase A-dependent 
      inhibition of CRM1-mediated export from the nucleus.
FAU - Chang, Ji Suk
AU  - Chang JS
AD  - Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical 
      Research Center, Baton Rouge, Louisiana 70808, USA.
FAU - Huypens, Peter
AU  - Huypens P
FAU - Zhang, Yubin
AU  - Zhang Y
FAU - Black, Chelsea
AU  - Black C
FAU - Kralli, Anastasia
AU  - Kralli A
FAU - Gettys, Thomas W
AU  - Gettys TW
LA  - eng
GR  - R01 DK064951/DK/NIDDK NIH HHS/United States
GR  - P20 RR021945/RR/NCRR NIH HHS/United States
GR  - 1P30 DK072476/DK/NIDDK NIH HHS/United States
GR  - DK064951/DK/NIDDK NIH HHS/United States
GR  - P20-RR021945/RR/NCRR NIH HHS/United States
GR  - P20 GM103528/GM/NIGMS NIH HHS/United States
GR  - R01 DK 074772/DK/NIDDK NIH HHS/United States
GR  - P30 DK072476/DK/NIDDK NIH HHS/United States
GR  - R01 DK074772/DK/NIDDK NIH HHS/United States
GR  - P30 GM118430/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20100329
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Karyopherins)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (Ppargc1a protein, mouse)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - CHO Cells
MH  - Cell Nucleus/*metabolism
MH  - Cricetinae
MH  - Cricetulus
MH  - Cyclic AMP-Dependent Protein Kinases/*metabolism
MH  - *Gene Expression Regulation
MH  - Karyopherins/*metabolism
MH  - Mice
MH  - Models, Biological
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
MH  - Receptors, Cytoplasmic and Nuclear/*metabolism
MH  - Sequence Homology, Nucleic Acid
MH  - Trans-Activators/*metabolism
MH  - Transcription Factors
MH  - Exportin 1 Protein
PMC - PMC2878565
EDAT- 2010/03/31 06:00
MHDA- 2010/06/25 06:00
PMCR- 2011/06/04
CRDT- 2010/03/31 06:00
PHST- 2010/03/31 06:00 [entrez]
PHST- 2010/03/31 06:00 [pubmed]
PHST- 2010/06/25 06:00 [medline]
PHST- 2011/06/04 00:00 [pmc-release]
AID - S0021-9258(19)35543-7 [pii]
AID - M109.083121 [pii]
AID - 10.1074/jbc.M109.083121 [doi]
PST - ppublish
SO  - J Biol Chem. 2010 Jun 4;285(23):18039-50. doi: 10.1074/jbc.M109.083121. Epub 2010 
      Mar 29.