Cell Cycle-Regulated Transcription through the FHA Domain of Fkh2p and the Coactivator Ndd1p

Darieva, Zoulfia; Pic‐Taylor, Aline; Boros, Joanna; Spanos, Adonis; Geymonat, Marco; Reece, Richard J.; Sedgwick, Steven G.; Sharrocks, Andrew D.; Morgan, Brian A.

doi:10.1016/j.cub.2003.08.053

Cited by 63 publications

(118 citation statements)

References 17 publications

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“…Another function of nuclear Clb2 might be the transcriptional control of key cell cycle regulators. Indeed, Clb2-Cdk1 complexes play an important role in the expression of the CLB2 cluster of genes through phosphorylation of the nuclear protein Ndd1, a co-activator of the transcription factor Mcm1-Fkh2 (Darieva et al, 2003). Considering the strong reduction of the nuclear Clb2 levels upon deletion of its NLS, one intriguing result of this study is the moderate G2-M delay of clb2 ⌬NLS cells, as compared to clb2⌬ cells.…”

Section: A Nuclear Function Of Clb2 In Anaphase Initiationmentioning

confidence: 76%

“…In this context, stabilization of Clb2 ⌬NLS might stem either from a lower accessibility of the mutant protein to the degradation machinery or from an altered APC Cdc20 activity. Indeed Cdk1 activates APC Cdc20 in at least two ways: the phosphorylation of several components of APC/C that is required for Cdc20-dependent APC activity (Rudner and Murray, 2000) and the transcriptional regulation of the CLB2 cluster of genes, which includes CDC20 (Spellman et al, 1998;Darieva et al, 2003). However, Pds1 was degraded with similar timing in clb1⌬ clb2…”

Section: Spatial Regulation Of Clb2 Proteolysismentioning

confidence: 99%

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Compartmentalization of the functions and regulation of the mitotic cyclin Clb2 inS. cerevisiae

Eluère

Offner

Varlet

et al. 2007

Journal of Cell Science

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Orderly progression through the eukaryotic cell cycle is a complex process involving both regulation of cyclin dependent kinase activity and control of specific substrate-Cdk interactions. In Saccharomyces cerevisiae, the mitotic cyclin Clb2 has a central role in regulating the onset of anaphase and in maintaining the cellular shape of the bud by inhibiting growth polarization induced in G1. However, how Clb2 and the partially redundant cyclin Clb1 confer specificity to Cdk1 in these processes still remains unclear. Here, we show that Clb2 mutants impaired in nuclear import or export are differentially affected for subsets of Clb2 functions while remaining fully functional for others. Our data support a direct role of the cytoplasmic pool of Clb1,2-Cdk1 in terminating cytoskeleton and growth polarization, independently of G1 cyclin transcriptional regulation. By contrast, the nuclear form of the cyclin is required for timely initiation of anaphase. Clb2 localization influences its stage-specific degradation as well. We report that Clb2 trapped in the cytoplasm is stabilized during anaphase but not at the time of mitotic exit. Altogether, our results demonstrate that the subcellular localization of the mitotic cyclin Clb2 is one of the key determinants of its biological function.

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Section: A Nuclear Function Of Clb2 In Anaphase Initiationmentioning

confidence: 76%

Section: Spatial Regulation Of Clb2 Proteolysismentioning

confidence: 99%

Compartmentalization of the functions and regulation of the mitotic cyclin Clb2 inS. cerevisiae

Eluère

Offner

Varlet

et al. 2007

Journal of Cell Science

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“…Thus, CLB2 expression is likely to be subjected to a positivefeedback loop (11,23,44,49) and may be regulated differently from other genes in the CLB2 cluster. Very little is understood about how this feedback loop is broken to repress expression during G 1 and S phase.Fkh1, like Fkh2, contains an FHA domain and can function redundantly with Fkh2 to maintain cell cycle-regulated gene expression through an interaction with Ndd1 at the SFF site (11,20,23,49). Despite this redundancy, Fkh1 and Fkh2 do not have equivalent functions, although precisely how Fkh1 functions remains to be defined.…”

mentioning

confidence: 99%

“…Ndd1 is a substrate for the Clb2/ Cdc28 G 2 /M kinase, and phosphorylation promotes the interaction between Ndd1 and the FHA domain of Fkh2 (11,49). Thus, CLB2 expression is likely to be subjected to a positivefeedback loop (11,23,44,49) and may be regulated differently from other genes in the CLB2 cluster. Very little is understood about how this feedback loop is broken to repress expression during G 1 and S phase.…”

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confidence: 99%

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

Sherriff

Kent

Mellor

2007

Molecular and Cellular Biology

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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 G 2 /M phase and repressed during G 1 . 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 G 1 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 G 2 /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 G 2 /M and to fully repress expression during G 1 .The forkhead (Fkh) family of transcription factors is highly conserved in eukaryotes, with roles in cell cycle control, cell death, proliferative responses, and differentiation (1,3,4,27). All four forkhead factors have been characterized in Saccharomyces cerevisiae. Fhl1 and its coregulator Ihf1 regulate cell proliferation primarily through control of ribosomal protein gene expression (5,18,21,35,50,52,59). Different phases of the cell cycle are regulated by two forkhead factors, Hcm1 and Fkh2. Hcm1 regulates chromosome segregation genes and controls the S-phase transition (46). Fkh2 and its coactivator Ndd1 influence the expression of a wide range of genes (56), including the genes of the CLB2 cluster that control the G 2 /M and M/G 1 phases of the cell cycle (15,23,62) which are the best-characterized targets of Fkh2/Ndd1 regulation. Genes belonging to the CLB2 cluster, including CLB2 itself, contain one or more SFF binding sites at which Fkh2, Ndd1, and the MADS box protein Mcm1 bind. Both Fkh2 and Ndd1 are subject to extensive phosphorylation during the cell cycle. The Clb5/Cdc28 complex phosphorylates residues on the C-terminal region of Fkh2 between the S phase and G 2 (44). The interaction between Fkh2 and Ndd1 is optimal when both proteins are phosphorylated. Ndd1 is a substrate for the Clb2/ Cdc28 G 2 /M kinase, and phosphorylation promotes the interaction between Ndd1 and the FHA domain of Fkh2 (11,49). Thus, CLB2 expression is likely to be subjected to a positivefeedback loop (11,23,44,49) and may be regulated differently from other genes in the CLB2 cluster. Very little is understood about how this feedback loop is broken to repres...

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The FHA Domain

Durocher¹

2004

Modular Protein Domains

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Cell Cycle-Regulated Transcription through the FHA Domain of Fkh2p and the Coactivator Ndd1p

Cited by 63 publications

References 17 publications

Compartmentalization of the functions and regulation of the mitotic cyclin Clb2 inS. cerevisiae

Compartmentalization of the functions and regulation of the mitotic cyclin Clb2 inS. cerevisiae

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

The FHA Domain

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