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

  title={AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1},
  author={Ren{\'e} H. Medema and Geert J.P.L. Kops and Johannes L Bos and Boudewijn M. T. Burgering},
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… 
Cell cycle and death control: long live Forkheads.
Control of Cell Cycle Exit and Entry by Protein Kinase B-Regulated Forkhead Transcription Factors
It is proposed that Forkhead inactivation by PKB signaling in quiescent cells is a crucial step in cell cycle reentry and contributes to the processes of transformation and regeneration.
FOXO Forkhead Transcription Factors Induce G2-M Checkpoint in Response to Oxidative Stress*
The results suggest that the FOXO family of transcription factors plays an important role in the regulation of GADD45 in response to oxidative stress and thereby contributes to G2-M checkpoint.
Forkhead Transcription Factors Are Critical Effectors of Cell Death and Cell Cycle Arrest Downstream of PTEN
It is shown that Forkhead transcription factors FKHRL1 and FKHR, substrates of the Akt kinase, are aberrantly localized to the cytoplasm and cannot activate transcription in PTEN-deficient cells.
Redox Regulation of Forkhead Proteins Through a p66shc-Dependent Signaling Pathway
It is demonstrated that p66shc regulates intracellular oxidant levels in mammalian cells and that hydrogen peroxide can negatively regulate forkhead activity, and that expression of FKHRL1 results in an increase in both hydrogenperoxide scavenging and oxidative stress resistance.
Regulation of the Forkhead Transcription Factor AFX by Ral-Dependent Phosphorylation of Threonines 447 and 451
It is concluded that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT.
The Forkhead Transcription Factor AFX Activates Apoptosis by Induction of the BCL-6 Transcriptional Repressor*
An AFX-regulated pathway that appears to account for at least part of this apoptotic regulatory system is described, suggesting that AFX regulates apoptosis in part by suppressing the levels of anti-apoptotic BCL-XL through the transcriptional repressor BCL6.
Forkhead transcription factors contribute to execution of the mitotic programme in mammals
The results support the important role of forkhead in the control of mammalian cell cycle completion, and suggest that efficient execution of the mitotic programme depends on downregulation of PI(3)K/PKB and consequent induction of FKH transcriptional activity.
Forkhead Family Transcription Factor FKHRL1 Is Expressed in Human Megakaryocytes
The results suggest that FKHRL1 plays an important role in the cell cycle of megakaryocytic cells as one of the downstream target molecules of phosphatidylinositol 3-kinase-Akt, presumably mediated through the activation or inactivation of cell cycle-associated gene(s).


Negative Regulation of the Forkhead Transcription Factor FKHR by Akt*
FKHR may be a direct nuclear regulatory target for Akt in both metabolic and cell survival pathways, and mutation of these three sites to alanine residues enhances the transcriptional activity of FKHR and renders it resistant to inhibition by Akt.
Direct control of the Forkhead transcription factor AFX by protein kinase B
It is shown that protein kinase B phosphorylates AFX, a human orthologue of daf -16, both in vitro and in vivo, delineate a pathway for PI(3)K-dependent signalling to the nucleus.
daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans.
The wild-type Caenorhabditis elegans nematode ages rapidly, undergoing development, senescence, and death in less than 3 weeks. In contrast, mutants with reduced activity of the gene daf-2, a homolog
Phosphorylation of the Transcription Factor Forkhead Family Member FKHR by Protein Kinase B*
FKHR, a human homologue of the DAF16 transcription factor in Caenorhabditis elegans, is rapidly phosphorylated by human protein kinase Bα (PKBα) at Thr-24, Ser-256, and Ser-319 in vitro and at a much faster rate than BAD, which is thought to be a physiological substrate for PKB.
Human cyclin E, a nuclear protein essential for the G1-to-S phase transition
It is found that mammalian cells express two forms of cyclin E protein which differ from each other by the presence or absence of a 15-amino-acid amino-terminal domain, and cyclins E and D1 control two different transitions within the human cell cycle.
The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans
It is shown that null mutations in Daf-16 suppress the effects of mutations in daf-2 or age-1; lack of dAF-16 bypasses the need for this insulin receptor-like signalling pathway.
p21waf1 can block cells at two points in the cell cycle, but does not interfere with processive DNA-replication or stress-activated kinases
It is concluded that, at least in these U2OS-derived cells, p21waf1 functions as an inhibitor of CDK-activity in G1 and G2, but not as an inhibitors of PCNA or SAPKs.
PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells.
  • D. Li, H. Sun
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 1998
It is shown that PTEN expression potently suppressed the growth and tumorigenicity of human glioblastoma U87MG cells, and studies suggest that the PTEN tumor suppressor modulates G1 cell cycle progression through negatively regulating the PI 3-kinase/Akt signaling pathway.