Forkhead Transcription Factors Block Cell Cycle

2000 ◽  
Vol 2000 (28) ◽  
pp. tw1-tw1
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Forkhead Transcription Factors

scholarly journals Cell Cycle Inhibition by FoxO Forkhead Transcription Factors Involves Downregulation of Cyclin D

2002 ◽  
Vol 22 (22) ◽  
pp. 7842-7852 ◽  
Author(s):  
Marc Schmidt ◽  
Sylvia Fernandez de Mattos ◽  
Armando van der Horst ◽  
Rob Klompmaker ◽  
Geert J. P. L Kops ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Protein Expression ◽  
Cell Cycle Arrest ◽  
Cellular Proliferation ◽  
Kinase Inhibitor ◽  
Ectopic Expression ◽  
Forkhead Transcription Factors ◽  
Cycle Arrest ◽  
Cell Cycle Inhibition

ABSTRACT The FoxO forkhead transcription factors FoxO4 (AFX), FoxO3a (FKHR.L1), and FoxO1a (FKHR) represent important physiological targets of phosphatidylinositol-3 kinase (PI3K)/protein kinase B (PKB) signaling. Overexpression or conditional activation of FoxO factors is able to antagonize many responses to constitutive PI3K/PKB activation including its effect on cellular proliferation. It was previously shown that the FoxO-induced cell cycle arrest is partially mediated by enhanced transcription and protein expression of the cyclin-dependent kinase inhibitor p27kip1 (R. H. Medema, G. J. Kops, J. L. Bos, and B. M. Burgering, Nature 404:782-787, 2000). Here we have identified a p27kip1-independent mechanism that plays an important role in the antiproliferative effect of FoxO factors. Forced expression or conditional activation of FoxO factors leads to reduced protein expression of the D-type cyclins D1 and D2 and is associated with an impaired capacity of CDK4 to phosphorylate and inactivate the S-phase repressor pRb. Downregulation of D-type cyclins involves a transcriptional repression mechanism and does not require p27kip1 function. Ectopic expression of cyclin D1 can partially overcome FoxO factor-induced cell cycle arrest, demonstrating that downregulation of D-type cyclins represents a physiologically relevant mechanism of FoxO-induced cell cycle inhibition.

scholarly journals Control of Cyclin G2 mRNA Expression by Forkhead Transcription Factors: Novel Mechanism for Cell Cycle Control by Phosphoinositide 3-Kinase and Forkhead

2004 ◽  
Vol 24 (5) ◽  
pp. 2181-2189 ◽  
Author(s):  
Lorena Martínez-Gac ◽  
Miriam Marqués ◽  
Zaira García ◽  
Miguel R. Campanero ◽  
Ana C. Carrera
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Mrna Expression ◽  
Mrna Levels ◽  
Expression Levels ◽  
Forkhead Transcription Factors ◽  
Cell Cycle Entry ◽  
Cyclin G2 ◽  
Phosphoinositide 3 Kinase ◽  
Mrna Expression Levels

ABSTRACT Cyclin G2 is an unconventional cyclin highly expressed in postmitotic cells. Unlike classical cyclins that promote cell cycle progression, cyclin G2 blocks cell cycle entry. Here we studied the mechanisms that regulate cyclin G2 mRNA expression during the cell cycle. Analysis of synchronized NIH 3T3 cell cultures showed elevated cyclin G2 mRNA expression levels at G0, with a considerable reduction as cells enter cell cycle. Downregulation of cyclin G2 mRNA levels requires activation of phosphoinositide 3-kinase, suggesting that this enzyme controls cyclin G2 mRNA expression. Because the phosphoinositide 3-kinase pathway inhibits the FoxO family of forkhead transcription factors, we examined the involvement of these factors in the regulation of cyclin G2 expression. We show that active forms of the forkhead transcription factor FoxO3a (FKHRL1) increase cyclin G2 mRNA levels. Cyclin G2 has forkhead consensus motifs in its promoter, which are transactivated by constitutive active FoxO3a forms. Finally, interference with forkhead-mediated transcription by overexpression of an inactive form decreases cyclin G2 mRNA expression levels. These results show that FoxO genes regulate cyclin G2 expression, illustrating a new role for phosphoinositide 3-kinase and FoxO transcription factors in the control of cell cycle entry.

scholarly journals Forkhead Transcription Factors Are Critical Effectors of Cell Death and Cell Cycle Arrest Downstream of PTEN

2000 ◽  
Vol 20 (23) ◽  
pp. 8969-8982 ◽  
Author(s):  
Noriaki Nakamura ◽  
Shivapriya Ramaswamy ◽  
Francisca Vazquez ◽  
Sabina Signoretti ◽  
Massimo Loda ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Transcription Factors ◽  
Cell Cycle Arrest ◽  
Transcriptional Activation ◽  
Active Form ◽  
Forkhead Transcription Factors ◽  
Cycle Arrest ◽  
In Cells ◽  
Constitutively Active

ABSTRACT PTEN acts as a tumor suppressor, at least in part, by antagonizing phosphoinositide 3-kinase (PI3K)/Akt signaling. Here we show 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. Restoration of PTEN function restores FKHR to the nucleus and restores transcriptional activation. Expression of a constitutively active form of FKHR that cannot be phosphorylated by Akt produces the same effect as reconstitution of PTEN on PTEN-deficient tumor cells. Specifically, activated FKHR induces apoptosis in cells that undergo PTEN-mediated cell death and induces G1 arrest in cells that undergo PTEN-mediated cell cycle arrest. Furthermore, both PTEN and constitutively active FKHR induce p27KIP1 protein but not p21. These data suggest that Forkhead transcription factors are critical effectors of PTEN-mediated tumor suppression.

scholarly journals A Forkhead Transcription Factor Is Important for True Hyphal as well as Yeast Morphogenesis in Candida albicans

2002 ◽  
Vol 1 (5) ◽  
pp. 787-798 ◽  
Author(s):  
Eric S. Bensen ◽  
Scott G. Filler ◽  
Judith Berman
Keyword(s):  
Cell Cycle ◽  
Candida Albicans ◽  
Transcription Factors ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Hyphal Growth ◽  
Growth Conditions ◽  
Yeast Cells ◽  
Cycle Progression ◽  
Forkhead Transcription Factors

ABSTRACT Candida albicans is an important pathogen of immunocompromised patients which grows with true hyphal, pseudohyphal, and yeast morphologies. The dynamics of cell cycle progression are markedly different in true hyphal relative to pseudohyphal and yeast cells, including nuclear movement and septin ring positioning. In Saccharomyces cerevisiae, two forkhead transcription factors (ScFKH1 and ScFKH2) regulate the expression of B-cyclin genes. In both S. cerevisiae and Schizosaccharomyces pombe, forkhead transcription factors also influence morphogenesis. To explore the molecular mechanisms that connect C. albicans morphogenesis with cell cycle progression, we analyzed CaFKH2, the single homolog of S. cerevisiae FKH1/FKH2. C. albicans cells lacking CaFkh2p formed constitutive pseudohyphae under all yeast and hyphal growth conditions tested. Under hyphal growth conditions levels of hyphae-specific mRNAs were reduced, and under yeast growth conditions levels of several genes encoding proteins likely to be important for cell wall separation were reduced. Together these results imply that Fkh2p is required for the morphogenesis of true hyphal as well as yeast cells. Efg1p and Cph1p, two transcription factors that contribute to C. albicans hyphal growth, were not required for the pseudohyphal morphology of fkh2 mutants, implying that Fkh2p acts in pathways downstream of and/or parallel to Efg1p and Cph1p. In addition, cells lacking Fkh2p were unable to damage human epithelial or endothelial cells in vitro, suggesting that Fkh2p contributes to C. albicans virulence.

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

Nature ◽  
2000 ◽  
Vol 404 (6779) ◽  
pp. 782-787 ◽  
Author(s):  
René H. Medema ◽  
Geert J. P. L. Kops ◽  
Johannes L. Bos ◽  
Boudewijn M. T. Burgering
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Cell Cycle Regulation ◽  
Forkhead Transcription Factors ◽  
Mediate Cell ◽  
Cycle Regulation

scholarly journals Quantitative model of eukaryotic Cdk control through the Forkhead CONTROLLER

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Matteo Barberis
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Cell Division ◽  
Design Principle ◽  
Budding Yeast ◽  
Eukaryotic Cell ◽  
Quantitative Model ◽  
Sequential Order ◽  
Forkhead Transcription Factors

AbstractIn budding yeast, synchronization of waves of mitotic cyclins that activate the Cdk1 kinase occur through Forkhead transcription factors. These molecules act as controllers of their sequential order and may account for the separation in time of incompatible processes. Here, a Forkhead-mediated design principle underlying the quantitative model of Cdk control is proposed for budding yeast. This design rationalizes timing of cell division, through progressive and coordinated cyclin/Cdk-mediated phosphorylation of Forkhead, and autonomous cyclin/Cdk oscillations. A “clock unit” incorporating this design that regulates timing of cell division is proposed for both yeast and mammals, and has a DRIVER operating the incompatible processes that is instructed by multiple CLOCKS. TIMERS determine whether the clocks are active, whereas CONTROLLERS determine how quickly the clocks shall function depending on external MODULATORS. This “clock unit” may coordinate temporal waves of cyclin/Cdk concentration/activity in the eukaryotic cell cycle making the driver operate the incompatible processes, at separate times.

scholarly journals 14-3-3 proteins: a family of versatile molecular regulators

2008 ◽  
pp. S11-S21
Author(s):  
V Obšilová ◽  
J Šilhan ◽  
E Bouřa ◽  
J Teisinger ◽  
T Obšil
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Cell Cycle Regulation ◽  
Molecular Scaffolds ◽  
Forkhead Transcription Factors ◽  
Binding Partners ◽  
Wide Range ◽  
Functional Modulation ◽  
Cycle Regulation ◽  
And Control

The 14-3-3 proteins are a family of acidic regulatory molecules found in all eukaryotes. 14-3-3 proteins function as molecular scaffolds by modulating the conformation of their binding partners. Through the functional modulation of a wide range of binding partners, 14-3-3 proteins are involved in many processes, including cell cycle regulation, metabolism control, apoptosis, and control of gene transcription. This minireview includes a short overview of 14-3-3 proteins and then focuses on their role in the regulation of two important binding partners: FOXO forkhead transcription factors and an enzyme tyrosine hydroxylase.

scholarly journals The Isw2 Chromatin-Remodeling ATPase Cooperates with the Fkh2 Transcription Factor To Repress Transcription of the B-Type Cyclin Gene CLB2

2007 ◽  
Vol 27 (8) ◽  
pp. 2848-2860 ◽  
Author(s):  
Julia A. Sherriff ◽  
Nicholas A. Kent ◽  
Jane Mellor
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Chromatin Remodeling ◽  
Coding Region ◽  
Related Factors ◽  
Forkhead Transcription Factors ◽  
Repressive Chromatin ◽  
Proliferation And Differentiation ◽  
M Phase ◽  
Cyclin Gene

ABSTRACT Forkhead (Fkh) transcription factors influence cell death, proliferation, and differentiation and the cell cycle. In Saccharomyces cerevisiae, Fkh2 both activates and represses transcription of CLB2, encoding a B-type cyclin. CLB2 is expressed during G2/M phase and repressed during G1. Fkh2 recruits the coactivator Ndd1, an interaction which is promoted by Clb2/Cdk1-dependent phosphorylation of Ndd1, suggesting that CLB2 is autoregulated. Ndd1 is proposed to function by antagonizing Fkh2-mediated repression, but nothing is known about the mechanism. Here we ask how Fkh2 represses CLB2. We show that Fkh2 controls a repressive chromatin structure that initiates in the early coding region of CLB2 and spreads up the promoter during the M and G1 phases. The Isw2 chromatin-remodeling ATPase cooperates with Fkh2 to remodel the chromatin and repress CLB2 expression throughout the cell cycle. In addition, the related factors Isw1 and Fkh1 configure the chromatin at the early coding region and negatively regulate CLB2 expression but only during G2/M phase. Thus, the cooperative actions of two forkhead transcription factors and two chromatin-remodeling ATPases combine to regulate CLB2. We propose that chromatin-mediated repression by Isw1 and Isw2 may serve to limit activation of CLB2 expression by the Clb2/Cdk1 kinase during G2/M and to fully repress expression during G1.

scholarly journals Control of Cell Cycle Exit and Entry by Protein Kinase B-Regulated Forkhead Transcription Factors

2002 ◽  
Vol 22 (7) ◽  
pp. 2025-2036 ◽  
Author(s):  
Geert J. P. L. Kops ◽  
Rene H. Medema ◽  
Janet Glassford ◽  
Marieke A. G. Essers ◽  
Pascale F. Dijkers ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Protein Kinase ◽  
Cell Cycle Arrest ◽  
Protein Kinase B ◽  
Human Colon ◽  
Inhibition Of Proliferation ◽  
Forkhead Transcription Factors ◽  
Cell Cycle Reentry ◽  
Cycle Arrest

ABSTRACT AFX-like Forkhead transcription factors, which are controlled by phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling, are involved in regulating cell cycle progression and cell death. Both cell cycle arrest and induction of apoptosis are mediated in part by transcriptional regulation of p27kip1. Here we show that the Forkheads AFX (FOXO4) and FKHR-L1 (FOXO3a) also directly control transcription of the retinoblastoma-like p130 protein and cause upregulation of p130 protein expression. Detailed analysis of p130 regulation demonstrates that following Forkhead-induced cell cycle arrest, cells enter G0 and become quiescent. This is shown by a change in phosphorylation of p130 to G0-specific forms and increased p130/E2F-4 complex formation. Most importantly, long-term Forkhead activation causes a sustained but reversible inhibition of proliferation without a marked increase in apoptosis. As for the activity of the Forkheads, we also show that protein levels of p130 are controlled by endogenous PI3K/PKB signaling upon cell cycle reentry. Surprisingly, not only nontransformed cells, but also cancer cells such as human colon carcinoma cells, are forced into quiescence by Forkhead activation. We therefore propose 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.

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