PMID- 20038583
OWN - NLM
STAT- MEDLINE
DCOM- 20100326
LR  - 20231213
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 285
IP  - 9
DP  - 2010 Feb 26
TI  - Map4k4 negatively regulates peroxisome proliferator-activated receptor (PPAR) 
      gamma protein translation by suppressing the mammalian target of rapamycin (mTOR) 
      signaling pathway in cultured adipocytes.
PG  - 6595-603
LID - 10.1074/jbc.M109.068502 [doi]
AB  - The receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is 
      considered a master regulator of adipocyte differentiation and promotes glucose 
      and lipid metabolism in mature adipocytes. We recently identified the yeast 
      Sterile 20 (Ste20) protein kinase ortholog, Map4k4, in an RNA interference-based 
      screen as an inhibitor of PPARgamma expression in cultured adipocytes. Here, we 
      show that RNA interference-mediated silencing of Map4k4 elevates the levels of 
      both PPARgamma1 and PPARgamma2 proteins in 3T3-L1 adipocytes without affecting 
      PPARgamma mRNA levels, suggesting that Map4k4 regulates PPARgamma at a 
      post-transcriptional step. PPARgamma degradation rates are remarkably rapid as 
      measured in the presence of cycloheximide (t(1/2) = 2 h), but silencing Map4k4 
      had no effect on PPARgamma degradation. However, depletion of Map4k4 
      significantly enhances [(35)S]methionine/cysteine incorporation into proteins, 
      suggesting that Map4k4 signaling decreases protein translation. We show a 
      function of Map4k4 is to inhibit rapamycin-sensitive mammalian target of 
      rapamycin (mTOR) activity, decreasing 4E-BP1 phosphorylation. In addition, our 
      results show mTOR and 4E-BP1 are required for the increased PPARgamma protein 
      expression upon Map4k4 knockdown. Consistent with this concept, 
      adenovirus-mediated expression of Map4k4 decreased PPARgamma protein levels and 
      mTOR phosphorylation. These data show that Map4k4 negatively regulates PPARgamma 
      post-transcriptionally, by attenuating mTOR signaling and a 4E-BP1-dependent 
      mechanism.
FAU - Guntur, Kalyani V P
AU  - Guntur KV
AD  - Program in Molecular Medicine, University of Massachusetts Medical School, 
      Worcester, Massachusetts 01605, USA.
FAU - Guilherme, Adilson
AU  - Guilherme A
FAU - Xue, Liting
AU  - Xue L
FAU - Chawla, Anil
AU  - Chawla A
FAU - Czech, Michael P
AU  - Czech MP
LA  - eng
GR  - DK030638-25/DK/NIDDK NIH HHS/United States
GR  - DK30898-25/DK/NIDDK NIH HHS/United States
GR  - P30 DK032520/DK/NIDDK NIH HHS/United States
GR  - R37 DK030898/DK/NIDDK NIH HHS/United States
GR  - R01 DK030898/DK/NIDDK NIH HHS/United States
GR  - DK032520/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20091228
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Eif4ebp1 protein, mouse)
RN  - 0 (Eukaryotic Initiation Factors)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (PPAR gamma)
RN  - 0 (Phosphoproteins)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - 3T3-L1 Cells
MH  - Adaptor Proteins, Signal Transducing
MH  - Adipocytes/cytology/*metabolism
MH  - Animals
MH  - Carrier Proteins/*metabolism
MH  - Cell Cycle Proteins
MH  - Eukaryotic Initiation Factors
MH  - Gene Expression Regulation
MH  - Intracellular Signaling Peptides and Proteins/*antagonists & inhibitors
MH  - Mice
MH  - PPAR gamma/*antagonists & inhibitors/biosynthesis
MH  - Phosphoproteins/*metabolism
MH  - Phosphorylation
MH  - Protein Serine-Threonine Kinases/*antagonists & inhibitors/*physiology
MH  - Protein Stability
MH  - *Signal Transduction
MH  - TOR Serine-Threonine Kinases
MH  - NF-kappaB-Inducing Kinase
PMC - PMC2825455
EDAT- 2009/12/30 06:00
MHDA- 2010/03/27 06:00
PMCR- 2011/02/26
CRDT- 2009/12/30 06:00
PHST- 2009/12/30 06:00 [entrez]
PHST- 2009/12/30 06:00 [pubmed]
PHST- 2010/03/27 06:00 [medline]
PHST- 2011/02/26 00:00 [pmc-release]
AID - S0021-9258(19)37826-3 [pii]
AID - M109.068502 [pii]
AID - 10.1074/jbc.M109.068502 [doi]
PST - ppublish
SO  - J Biol Chem. 2010 Feb 26;285(9):6595-603. doi: 10.1074/jbc.M109.068502. Epub 2009 
      Dec 28.