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PMID: 10377430 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 96 ·No. 13 ·1999-06-22 ·Pages 7421-6

Biggs WH, Meisenhelder J, Hunter T, Cavenee WK, Arden KC

Abstract

Although genetic analysis has demonstrated that members of the winged helix, or forkhead, family of transcription factors play pivotal roles in the regulation of cellular differentiation and proliferation, both during development and in the adult, little is known of the mechanisms underlying their regulation. Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. These results indicate that phosphorylation by PKB/Akt negatively regulates FKHR1 by promoting export from the nucleus.

MeSH Terms
Animals Biological Transport/genetics Cell Line Cell Nucleus/metabolism DNA-Binding Proteins/genetics,metabolism Gene Expression Regulation Mutation Phosphatidylinositol 3-Kinases/metabolism Phosphorylation Protein Serine-Threonine Kinases Proto-Oncogene Proteins/genetics,metabolism Proto-Oncogene Proteins c-akt Recombinant Proteins/genetics,metabolism Transcription Factors/genetics,metabolism
Chemicals
DNA-Binding Proteins Proto-Oncogene Proteins Recombinant Proteins Transcription Factors Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Biggs W H
The Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093-0660, USA. [email protected]
Meisenhelder J
Hunter T
Cavenee W K
Arden K C
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.96.13.7421
Email
[email protected]
Published
1999-06-22
Pages
7421-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC22101
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.96.13.7421 PMC Full Text View journal details
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