Two conserved modules of Schizosaccharomyces pombe Mediator regulate distinct cellular pathways

Linder, Tomas; Rasmussen, Nina N.; Samuelsen, Camilla O.; Chatzidaki, Emmanouella E.; Baraznenok, Vera; Bève, Jenny; Henriksen, Peter; Gustafsson, Claes M.; Holmberg, Steen

doi:10.1093/nar/gkn070

Cited by 30 publications

(77 citation statements)

References 67 publications

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“…Unlike Cdk1 or the Polo kinases, Cdk8 does not seem to be required for gene activation per se, since the levels of Mediator binding and mitotic gene transcription remain largely unchanged in the Cdk8 kinase mutant. This observation also explains the relative mild effects on mitotic genes observed in earlier microarray studies performed using nonsynchronized cdk8-D158A cells (30).…”

Section: Discussionsupporting

confidence: 72%

“…The Cdk8 kinase is an integral part of the Mediator complex (9), and the observed requirement for the cdk8 kinase activity for normal mitotic entry could therefore be connected to a function of the Cdk8/Mediator complex during mitotic transcription. Although a direct role for the Mediator complex in periodic transcription has not been reported, earlier microarray studies performed with nonsynchronized cells have revealed alterations of mitotic transcript levels in Mediator mutant strains (30,35). In fission yeast, expression of a specific subset of genes (cluster 1) is initiated as cells pass through mitosis (49).…”

Section: Inactivation Of the Cdk8 Kinase Activity Delays Mitotic Entrymentioning

confidence: 99%

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Cyclin-Dependent Kinase 8 Regulates Mitotic Commitment in Fission Yeast

Szilágyi

Bányai

López

et al. 2012

Molecular and Cellular Biology

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Temporal changes in transcription programs are coupled to control of cell growth and division. We here report that Mediator, a conserved coregulator of eukaryotic transcription, is part of a regulatory pathway that controls mitotic entry in fission yeast. The Mediator subunit cyclin-dependent kinase 8 (Cdk8) phosphorylates the forkhead 2 (Fkh2) protein in a periodic manner that coincides with gene activation during mitosis. Phosphorylation prevents degradation of the Fkh2 transcription factor by the proteasome, thus ensuring cell cycle-dependent variations in Fkh2 levels. Interestingly, Cdk8-dependent phosphorylation of Fkh2 controls mitotic entry, and mitotic entry is delayed by inactivation of the Cdk8 kinase activity or mutations replacing the phosphorylated serine residues of Fkh2. In addition, mutations in Fkh2, which mimic protein phosphorylation, lead to premature mitotic entry. Therefore, Fkh2 regulates not only the onset of mitotic transcription but also the correct timing of mitotic entry via effects on the Wee1 kinase. Our findings thus establish a new pathway linking the Mediator complex to control of mitotic transcription and regulation of mitotic entry in fission yeast. Signaling pathways can control the activation of gene expression programs and thereby regulate cell fate determination. In embryonic stem cells, certain gene expression programs allow the cells to self-renew whereas other programs trigger differentiation into specific cell types as a response to developmental signaling (58). Elucidation of how temporal changes in transcription programs are coupled to control of cell growth and division is therefore of fundamental importance for our understanding of developmental processes.Global gene transcription analysis in yeasts and higher eukaryotes has revealed that a significant proportion of the genome is transcribed in a periodic manner during cell cycle progression (5,15,34,49,55). Correct periodic regulation is believed to play a critical role in normal cell proliferation, and the genes are often deregulated in different forms of cancer (6). Depending on the organism, the number of periodically expressed genes ranges from ϳ400 to more than 1,000 (5, 6, 56). These include genes with well-established roles in cell cycle progression, such as those encoding cyclins, transcription factors and protein kinases.A cluster named CLB2 in budding yeast (35 genes) or cluster 1 in fission yeast (87 genes) is periodically expressed and activated at mitosis and repressed in G 1 of the next cell cycle (4,5,34,56). In budding yeast, transcription of the CLB2 cluster is controlled by the forkhead proteins Fkh1 and Fkh2, which cooperate with Mcm1 (a MADS box protein) and the Ndd1 coactivator (27, 28). In fission yeast, forkhead proteins Sep1 and Fkh2 and the MADS box protein Mbx1 regulate mitotic transcription (12,13,49,53). Deletion of the sep1 gene results in reduced transcription, whereas overexpression of sep1 induces expression of the same genes. In contrast, deletion of fkh2 causes elevated levels of g...

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Section: Discussionsupporting

confidence: 72%

Section: Inactivation Of the Cdk8 Kinase Activity Delays Mitotic Entrymentioning

confidence: 99%

Cyclin-Dependent Kinase 8 Regulates Mitotic Commitment in Fission Yeast

Szilágyi

Bányai

López

et al. 2012

Molecular and Cellular Biology

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“…To further link Mediator to mitotic transcription of the ace2 ϩ gene, we analyzed the effects of med15 ϩ and med20 ϩ deletions on ace2 transcription and Mediator binding in synchronized cells. These gene deletions were selected because previous genome-wide transcription analyses had demonstrated that deletion of med20 ϩ affects the transcription of a number of mitotic genes in unsynchronized cells (36,37) and that loss of Med15 causes a cell separation phenotype similar to that observed for sep1⌬ (36). We found that loss of Med20 abolished cell cycledependent variations in Mediator binding at the ace2 ϩ promoter (Fig.…”

Section: Fkh2 Affects the Timing Of Mediator Recruitment And Ace2mentioning

confidence: 69%

Mediator Can Regulate Mitotic Entry and Direct Periodic Transcription in Fission Yeast

Bányai

López

Szilágyi

et al. 2014

Molecular and Cellular Biology

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Cdk8 is required for correct timing of mitotic progression in fission yeast. How the activity of Cdk8 is regulated is unclear, since the kinase is not activated by T-loop phosphorylation and its partner, CycC, does not oscillate. Cdk8 is, however, a component of the multiprotein Mediator complex, a conserved coregulator of eukaryotic transcription that is connected to a number of intracellular signaling pathways. We demonstrate here that other Mediator components regulate the activity of Cdk8 in vivo and thereby direct the timing of mitotic entry. Deletion of Mediator components Med12 and Med13 leads to higher cellular Cdk8 protein levels, premature phosphorylation of the Cdk8 target Fkh2, and earlier entry into mitosis. We also demonstrate that Mediator is recruited to clusters of mitotic genes in a periodic fashion and that the complex is required for the transcription of these genes. We suggest that Mediator functions as a hub for coordinated regulation of mitotic progression and cell cycle-dependent transcription. The many signaling pathways and activator proteins shown to function via Mediator may influence the timing of these cell cycle events.

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“…Neither med15 ϩ nor hrp1 ϩ is essential for cell growth, and expression analysis has been used previously to discern S. pombe Mediator organization (16). Deletion of hrp1 ϩ had a milder effect on global gene transcription, but the data revealed a highly significant overlap (p ϭ 3.74 ϫ 10 Ϫ17 ) between genes up-regulated 2-fold or more in the ⌬hrp1 and ⌬med15 strains (Fig.…”

Section: Hrp1 Influences the Expression Of A Subset Of Med15-dependentmentioning

confidence: 92%

“…In support of this notion, structural analysis of the S. pombe S-Mediator only reveals the existence of a head and middle domain (10). However, even if there is no tail domain in S. pombe Mediator, the genome does encode for a putative Med15 homologue (SPBC146.01) (16). A role for fission yeast Med15 in Mediator function remains to be established.…”

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confidence: 99%