Forkhead transcription factors contribute to execution of the mitotic programme in mammals

Álvarez, Beatriz; Martı́nez-A, Carlos; Burgering, Boudewijn M.T.; Carrera, Ana C.

doi:10.1038/35099574

Cited by 260 publications

(280 citation statements)

References 28 publications

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“…Activation of FoxO3a during S phase transition will induce a G2/M cell cycle arrest, although this effect may not be mutually exclusive with the regulation of G1/S phase transition by FoxO. In contrast, a prior report has demonstrated that FoxO proteins activate the expression of genes, such as cyclin B and polo-like kinase, important for G2 and M phase progression (Alvarez et al, 2001). If this were true, then FoxO expression would appear to arrest cells at G1, while at the same time promoting cell cycle progression during G2 and M phases.…”

Section: Foxo and The G1/s Phase Transitionmentioning

confidence: 89%

Many forks in the path: cycling with FoxO

2008

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FoxO transcription factors are an evolutionary conserved subfamily of the forkhead transcription factors, characterized by the forkhead DNA-binding domain. FoxO factors regulate a number of cellular processes involved in cell-fate decisions in a cell-type-and environment-specific manner, including metabolism, differentiation, apoptosis and proliferation. A key mechanism by which FoxO determines cell fate is through regulation of the cell cycle machinery, and as such the cellular consequence of FoxO deregulation is often manifested through perturbation of the cell cycle. Consequently, the deregulation of FoxO factors is implicated in the development of numerous proliferative diseases, in particular cancer.

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Section: Foxo and The G1/s Phase Transitionmentioning

confidence: 89%

Many forks in the path: cycling with FoxO

2008

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“…Similarly, the effects of FOXO proteins on cell cycle progression are conflicting. Whereas most reports suggest that active FOXO proteins cause a cell cycle arrest (either a G1 arrest [Medema et al, 2000] or a G2/M arrest [Furukawa-Hibi et al, 2002;Tran et al, 2002]), one study showed that an active FOXO protein actually facilitates the M/G1 transition (Alvarez et al, 2001). For another forkhead protein, FOXM1b, such a cell cycle promoting affect is the accepted mode of action (Wang et al, 2002).…”

Section: Functional Conservation Of Forkhead Protein Roles In Oxidatimentioning

confidence: 99%

“…In Saccharomyces cerevisiae, only these latter two (of four forkhead homologues) are implicated in cell cycle regulation. In mammals, within which this family has expanded to include ϳ40 members (Carlsson and Mahlapuu, 2002), there are at least two subfamilies, FOXO (including four members) and FOXM (including only FOXM1), that are involved in cell cycle regulation (Medema et al, 2000;Alvarez et al, 2001;Tran et al, 2002;Wang et al, 2002). The FOXO proteins, much like their Caenorhabditis elegans homologue Daf-16, are known to respond to oxidative stress and are crucial for cellular protection from oxidative stress (Kops et al, 2002;Nemoto and Finkel, 2002;Murphy et al, 2003;Brunet et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Disruption of Yeast Forkhead-associated Cell Cycle Transcription by Oxidative Stress

Shapira

Segal

Botstein

2004

MBoC

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The effects of oxidative stress on yeast cell cycle depend on the stress-exerting agent. We studied the effects of two oxidative stress agents, hydrogen peroxide (HP) and the superoxide-generating agent menadione (MD). We found that two small coexpressed groups of genes regulated by the Mcm1-Fkh2-Ndd1 transcription regulatory complex are sufficient to account for the difference in the effects of HP and MD on the progress of the cell cycle, namely, G1 arrest with MD and an S phase delay followed by a G2/M arrest with HP. Support for this hypothesis is provided by fkh1fkh2 double mutants, which are affected by MD as we find HP affects wild-type cells. The apparent involvement of a forkhead protein in HP-induced cell cycle arrest, similar to that reported for Caenorhabditis elegans and human, describes a potentially novel stress response pathway in yeast. INTRODUCTIONReactive oxygen species (ROS) are by-products of aerobic metabolism, but are also attributes of the extracellular environment. They pose a threat to organisms by damaging a variety of cellular macromolecules, including DNA, membrane lipids, and proteins and are implicated with carcinogenesis, aging, and numerous degenerative diseases (Finkel and Holbrook, 2000;Neumann et al., 2003). The major ROS derived from oxygen are superoxide ions, hydrogen peroxide (HP), and hydroxy radicals, ordered here by increasing reactivity (reviewed in Shackelford et al., 2000).Oxidative stress in yeast has been studied by exposing cells to agents that are already reactive, typically HP, or drugs that cause the intracellular accumulation of reactive oxygen species (Godon et al., 1998;Dumond et al., 2000;Gasch et al., 2000). Menadione (MD) is such a drug, generating reactive superoxide ions, which can be further oxidized to give HP (Monks et al., 1992;Shackelford et al., 2000). It has been previously reported that exposure to HP or MD results in a cell cycle arrest (Flattery-O'Brien and Dawes, 1998;Leroy et al., 2001). However, the arrest points are not similar for the two agents. MD was reported to arrest cells at the G1 phase of the cell cycle, whereas HP was suggested to cause a G2 arrest by an alternate mechanism from that affected by MD (Flattery-O'Brien and Dawes, 1998); others reported that HP exposure causes a delay in the S phase (Leroy et al., 2001).Hundreds of genes are regulated so that they are expressed at specific times in the cell cycle and not at others (Cho et al., 1998;Spellman et al., 1998). The major part of this coordination is achieved by the sequential activation of a small number of transcription regulators (reviewed in Mendenhall and Hodge, 1998): MBF (a complex of Mbp1p and Swi6p) and SBF (a complex of Swi4p and Swi6p) are responsible for activating G1 transcription (Koch et al., 1993); Fkh1p and a complex formed by the cooperative promoter binding of Mcm1p and Fkh2p and a later recruitment of Ndd1p are responsible for activating G2/M transcription (Koranda et al., 2000;Kumar et al., 2000;Pic et al., 2000;Hollenhorst et al., 2001); Swi5p and Ace2p...

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“…Also, it was shown that Akt activation could overcome a G 2 /M cell cycle checkpoint induced by DNA damage (Kandel et al, 2002). Though PI3-K/Akt activity might be important for G 2 /M progression, it must be later transiently inactivated for mitotic exit, as the constitutive activation of this pathway leads to G 2 /M cell cycle arrest in an FKHRL1/Cyclin B/PLK dependent manner (Alvarez et al, 2001). …”

Section: Pi3-k/akt Pathway and Cell Cycle Progressionmentioning

confidence: 99%

Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy

Maddika¹,

Ande²,

Panigrahi³

et al. 2007

Drug Resistance Updates

403

302

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The partial cross-utilization of molecules and pathways involved in opposing processes like cell survival, proliferation and cell death, assures that mutations within one signaling cascade will also affect the other opposite process at least to some extent, thus contributing to homeostatic regulatory circuits. This review highlights some of the connections between opposite-acting pathways. Thus, we discuss the role of cyclins in the apoptotic process, and in the regulation of cell proliferation. CDKs and their inhibitors like the INK4-family (p16 Ink4a , p15 Ink4b , p18 Ink4c , p19 Ink4d ), and the Cip1/Waf1/Kip1-2-family (p21 Cip1/Waf1 , p27 Kip1 , p57 Kip2 ) are shown both in the context of proliferation regulators and as contributors to the apoptotic machinery. Bcl2-family members (i.e. Bcl2, Bcl-X L Mcl-1 L ; Bax, Bok/Mtd, Bak, and Bcl-X S ; Bad, Bid, Bim EL , Bmf, Mcl-1 S ) are highlighted both for their apoptosis-regulating capacity and also for their effect on the cell cycle progression. The PI3-K/Akt cell survival pathway is shown as regulator of cell metabolism and cell survival, but examples are also provided where aberrant activity of the pathway may contribute to the induction of apoptosis. Myc/Mad/Max proteins are shown both as a powerful S-phase driving complex and as apoptosis-sensitizers. We also discuss multifunctional proteins like p53 and Rb (RBL1/p107, RBL2/p130) both in the context of G 1 -S transition and as apoptotic triggers. Finally, we reflect on novel therapeutic approaches that would involve redirecting over-active survival and proliferation pathways towards induction of apoptosis in cancer cells.

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Forkhead transcription factors contribute to execution of the mitotic programme in mammals

Cited by 260 publications

References 28 publications

Many forks in the path: cycling with FoxO

Many forks in the path: cycling with FoxO

Disruption of Yeast Forkhead-associated Cell Cycle Transcription by Oxidative Stress

Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy

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