PMID- 10187842
OWN - NLM
STAT- MEDLINE
DCOM- 19990503
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 15
DP  - 1999 Apr 9
TI  - Regulation of the transcriptional activity of the peroxisome
      proliferator-activated receptor alpha by phosphorylation of a ligand-independent 
      trans-activating domain.
PG  - 10505-10
AB  - The peroxisome proliferator-activated receptors (PPARs) are a subgroup of nuclear
      receptors activated by fatty acids and eicosanoids. In addition, they are subject
      to phosphorylation by insulin, resulting in the activation of PPARalpha, while
      inhibiting PPARgamma under certain conditions. However, it was hitherto unclear
      whether the stimulatory effect of insulin on PPARalpha was direct and by which
      mechanism it occurs. We now demonstrate that amino acids 1-92 of hPPARalpha
      contain an activation function (AF)-1-like domain, which is further activated by 
      insulin through a pathway involving the mitogen-activated protein kinases p42 and
      p44. Further analysis of the amino-terminal region of PPARalpha revealed that the
      insulin-induced trans-activation occurs through the phosphorylation of two
      mitogen-activated protein kinase sites at positions 12 and 21, both of which are 
      conserved across evolution. The characterization of a strong AF-1 region in
      PPARalpha, stimulating transcription one-fourth as strongly as the viral protein 
      VP16, is compatible with the marked basal transcriptional activity of this
      isoform in transfection experiments. However, it is intriguing that the activity 
      of this AF-1 region is modulated by the phosphorylation of two serine residues,
      both of which must be phosphorylated in order to activate transcription. This is 
      in contrast to PPARgamma2, which was previously shown to be phosphorylated at a
      single site in a motif that is not homologous to the sites now described in
      PPARalpha. Although the molecular details involved in the
      phosphorylation-dependent enhancement of the transcriptional activity of
      PPARalpha remain to be elucidated, we demonstrate that the effect of insulin on
      the AF-1 region of PPARalpha can be mimicked by the addition of triiodothyronine 
      receptor beta1, a strong binder of corepressor proteins. In addition, a
      triiodothyronine receptor beta1 mutant deficient in interacting with corepressors
      is unable to activate PPARalpha. These observations suggest that the AF-1 region 
      of PPARalpha is partially silenced by corepressor proteins, which might interact 
      in a phosphorylation-dependent manner.
FAU - Juge-Aubry, C E
AU  - Juge-Aubry CE
AD  - Division of Endocrinology and Diabetes, University Hospital Geneva, CH-1211
      Geneva 14, Switzerland.
FAU - Hammar, E
AU  - Hammar E
FAU - Siegrist-Kaiser, C
AU  - Siegrist-Kaiser C
FAU - Pernin, A
AU  - Pernin A
FAU - Takeshita, A
AU  - Takeshita A
FAU - Chin, W W
AU  - Chin WW
FAU - Burger, A G
AU  - Burger AG
FAU - Meier, C A
AU  - Meier CA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Insulin)
RN  - 0 (Ligands)
RN  - 0 (NCOR1 protein, human)
RN  - 0 (Ncor1 protein, mouse)
RN  - 0 (Ncor1 protein, rat)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Nuclear Receptor Co-Repressor 1)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Repressor Proteins)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Calcium-Calmodulin-Dependent Protein Kinases/metabolism
MH  - Cells, Cultured
MH  - Consensus Sequence
MH  - Humans
MH  - Insulin/metabolism
MH  - Ligands
MH  - Mice
MH  - Molecular Sequence Data
MH  - Nuclear Proteins/metabolism
MH  - Nuclear Receptor Co-Repressor 1
MH  - Phosphorylation
MH  - Rats
MH  - Receptors, Cytoplasmic and Nuclear/genetics/*metabolism
MH  - Repressor Proteins/metabolism
MH  - Sequence Alignment
MH  - Transcription Factors/genetics/*metabolism
MH  - *Transcriptional Activation
EDAT- 1999/04/03 00:00
MHDA- 1999/04/03 00:01
CRDT- 1999/04/03 00:00
PHST- 1999/04/03 00:00 [pubmed]
PHST- 1999/04/03 00:01 [medline]
PHST- 1999/04/03 00:00 [entrez]
AID - 10.1074/jbc.274.15.10505 [doi]
AID - S0021-9258(19)73740-5 [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Apr 9;274(15):10505-10. doi: 10.1074/jbc.274.15.10505.