AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1

Nature. 2000 Apr 13;404(6779):782-7. doi: 10.1038/35008115.

Abstract

The Forkhead transcription factors AFX, FKHR and FKHR-L1 are orthologues of DAF-16, a Forkhead factor that regulates longevity in Caenorhabditis elegans. Here we show that overexpression of these Forkhead transcription factors causes growth suppression in a variety of cell lines, including a Ras-transformed cell line and a cell line lacking the tumour suppressor PTEN. Expression of AFX blocks cell-cycle progression at phase G1, independent of functional retinoblastoma protein (pRb) but dependent on the cell-cycle inhibitor p27kip1. Indeed, AFX transcriptionally activates p27kip1, resulting in increased protein levels. We conclude that AFX-like proteins are involved in cell-cycle regulation and that inactivation of these proteins is an important step in oncogenic transformation.

MeSH terms

  • 3T3 Cells
  • Animals
  • Blood Proteins / genetics
  • Blood Proteins / physiology*
  • Caenorhabditis elegans
  • Cell Cycle / physiology*
  • Cell Cycle Proteins*
  • Cell Division
  • Cell Line
  • Cell Transformation, Neoplastic
  • Cyclin-Dependent Kinase Inhibitor p27
  • DNA-Binding Proteins / metabolism
  • Enzyme Activation
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • G1 Phase / physiology
  • Gene Expression Regulation
  • Humans
  • Mice
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Mutation
  • PTEN Phosphohydrolase
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins*
  • ras Proteins / metabolism*

Substances

  • Blood Proteins
  • Cdkn1b protein, mouse
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • FOXO1 protein, human
  • FOXO4 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Microtubule-Associated Proteins
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • ras Proteins