PMID- 10358076
OWN - NLM
STAT- MEDLINE
DCOM- 19990706
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 24
DP  - 1999 Jun 11
TI  - Phosphorylation of serine 256 by protein kinase B disrupts transactivation by
      FKHR and mediates effects of insulin on insulin-like growth factor-binding
      protein-1 promoter activity through a conserved insulin response sequence.
PG  - 17184-92
AB  - Insulin inhibits the expression of multiple genes in the liver containing an
      insulin response sequence (IRS) (CAAAA(C/T)AA), and we have reported that protein
      kinase B (PKB) mediates this effect of insulin. Genetic studies in Caenorhabditis
      elegans indicate that daf-16, a forkhead/winged-helix transcription factor, is a 
      major target of the insulin receptor-PKB signaling pathway. FKHR, a human
      homologue of daf-16, contains three PKB sites and is expressed in the liver.
      Reporter gene studies in HepG2 hepatoma cells show that FKHR stimulates
      insulin-like growth factor-binding protein-1 promoter activity through an IRS,
      and introduction of IRSs confers this effect on a heterologous promoter. Insulin 
      disrupts IRS-dependent transactivation by FKHR, and phosphorylation of Ser-256 by
      PKB is necessary and sufficient to mediate this effect. Antisense studies
      indicate that FKHR contributes to basal promoter function and is required to
      mediate effects of insulin and PKB on promoter activity via an IRS. To our
      knowledge, these results provide the first report that FKHR stimulates promoter
      activity through an IRS and that phosphorylation of FKHR by PKB mediates effects 
      of insulin on gene expression. Signaling to FKHR-related forkhead proteins via
      PKB may provide an evolutionarily conserved mechanism by which insulin and
      related factors regulate gene expression.
FAU - Guo, S
AU  - Guo S
AD  - University of Illinois College of Medicine at Chicago and Chicago Area Veterans
      Health Care System (West Side Division), Chicago, Illinois 60612, USA.
FAU - Rena, G
AU  - Rena G
FAU - Cichy, S
AU  - Cichy S
FAU - He, X
AU  - He X
FAU - Cohen, P
AU  - Cohen P
FAU - Unterman, T
AU  - Unterman T
LA  - eng
GR  - DK41430/DK/NIDDK NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (FOXO1 protein, human)
RN  - 0 (Forkhead Box Protein O1)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Insulin)
RN  - 0 (Insulin-Like Growth Factor Binding Protein 1)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Amino Acid Sequence
MH  - Base Sequence
MH  - Conserved Sequence
MH  - DNA-Binding Proteins/genetics/*metabolism
MH  - Forkhead Box Protein O1
MH  - Forkhead Transcription Factors
MH  - Humans
MH  - Insulin/*pharmacology
MH  - Insulin-Like Growth Factor Binding Protein 1/*biosynthesis/genetics
MH  - Liver/cytology/*metabolism
MH  - Nuclear Proteins/genetics
MH  - Phosphorylation
MH  - Promoter Regions, Genetic
MH  - *Protein-Serine-Threonine Kinases
MH  - Proto-Oncogene Proteins/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Recombinant Proteins/metabolism
MH  - *Response Elements
MH  - Sequence Homology, Amino Acid
MH  - Signal Transduction
MH  - Transcription Factors/genetics/*metabolism
MH  - Transcriptional Activation
MH  - Tumor Cells, Cultured
EDAT- 1999/06/08 00:00
MHDA- 1999/06/08 00:01
CRDT- 1999/06/08 00:00
PHST- 1999/06/08 00:00 [pubmed]
PHST- 1999/06/08 00:01 [medline]
PHST- 1999/06/08 00:00 [entrez]
AID - 10.1074/jbc.274.24.17184 [doi]
AID - S0021-9258(19)72897-X [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Jun 11;274(24):17184-92. doi: 10.1074/jbc.274.24.17184.