Spatial Regulation of lag-2 Transcription During Vulval Precursor Cell Fate Patterning in Caenorhabditis  elegans
 lag-2

Zhang, Xinyong; Greenwald, Iva

doi:10.1534/genetics.111.128389

Cited by 39 publications

(62 citation statements)

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“…Third, the CKM appears to act as a corepressor of the Ets-family transcription factor LIN-1, as loss of cdk-8 or mdt-13/let-19 enhances the ectopic vulval induction caused by lin-1 reduction of function, and cdk-8 is required for full repression of a direct LIN-1 target promoter. Fourth, ectopic vulva formation in mdt-13/let-19 is independent of the Mediator subunit mdt-23/sur-2, which is critical for EGFR signaling-driven transcription and vulval development in wild-type worms (Singh and Han 1995;Zhang and Greenwald 2011); instead, mdt-13/let-19 modulates the specificity of the tail module triad subunits mdt-15, mdt-29, and mdt-27, preventing aberrant activation of downstream transcription. By implicating all CKM subunits and by connecting the CKM to lin-1 and to core Mediator, our data substantially expand on the prior finding that loss of CKM subunit mdt-12 caused ectopic vulva formation by unknown molecular mechanisms (Moghal and Sternberg 2003a).…”

Section: Discussionmentioning

confidence: 99%

“…In wild-type animals, a lag-2P(min)::YFP minimal promoter reporter (arEx1098) is induced by EGFR signaling in P6.p, whereas in lin-1 null mutants, it is ectopically induced in additional VPCs (Zhang and Greenwald 2011). We again used the lin-15A sensitized background to study cdk-8 requirements for lag-2P(min) repression.…”

Section: Cdk-8 Activity Is Kinase Dependentmentioning

confidence: 99%

“…The lag-2 minimal promoter contains activator and repressor elements, VPCact and VPCrep, that cooperatively restrict expression to P6.p (Zhang and Greenwald 2011). On its own, VPCact is sufficient to drive transcription in all VPCs (P3.p-P8.p) in a LIN-3/EGF ligand-independent manner.…”

Section: The Ckm Promotes Lin-1/ets Repressor Activitymentioning

confidence: 99%

“…Furthermore, the Mediator subunits mdt-23/sur-2, mdt-24/lin-25, and mdt-6 promote vulva development, whereas the CKM subunit mdt-12/dpy-22 inhibits vulva development in an anchor cell-independent manner (reviewed in Grants et al 2015); for standardized Mediator subunit nomenclature, please see Bourbon et al (2004). The mechanism by which mdt-23/sur-2 promotes vulva development has been partially elucidated, as it is a critical coactivator of a target gene downstream of the EGFR signaling pathway, the lag-2 Notch ligand gene (Zhang and Greenwald 2011). The lin-1/Ets effector transcription factor is similarly required to repress the lag-2 gene (Zhang and Greenwald 2011), raising the question of whether and how Mediator and LIN-1 interact to control common target genes.…”

mentioning

confidence: 99%

“…The mechanism by which mdt-23/sur-2 promotes vulva development has been partially elucidated, as it is a critical coactivator of a target gene downstream of the EGFR signaling pathway, the lag-2 Notch ligand gene (Zhang and Greenwald 2011). The lin-1/Ets effector transcription factor is similarly required to repress the lag-2 gene (Zhang and Greenwald 2011), raising the question of whether and how Mediator and LIN-1 interact to control common target genes. The other three Mediator subunits implicated in vulva development (mdt-6, mdt-12/ dpy-22, and mdt-24/lin-25) interact genetically with components of the EGFR signaling pathway, but their mode of action within this pathway remain poorly understood.…”

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confidence: 99%

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The Mediator Kinase Module Restrains Epidermal Growth Factor Receptor Signaling and Represses Vulval Cell Fate Specification in Caenorhabditis elegans

et al. 2015

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Cell signaling pathways that control proliferation and determine cell fates are tightly regulated to prevent developmental anomalies and cancer. Transcription factors and coregulators are important effectors of signaling pathway output, as they regulate downstream gene programs. In Caenorhabditis elegans, several subunits of the Mediator transcriptional coregulator complex promote or inhibit vulva development, but pertinent mechanisms are poorly defined. Here, we show that Mediator's dissociable cyclin dependent kinase 8 (CDK8) module (CKM), consisting of cdk-8, cic-1/Cyclin C, mdt-12/dpy-22, and mdt-13/let-19, is required to inhibit ectopic vulval cell fates downstream of the epidermal growth factor receptor (EGFR)-Ras-extracellular signal-regulated kinase (ERK) pathway. cdk-8 inhibits ectopic vulva formation by acting downstream of mpk-1/ERK, cell autonomously in vulval cells, and in a kinasedependent manner. We also provide evidence that the CKM acts as a corepressor for the Ets-family transcription factor LIN-1, as cdk-8 promotes transcriptional repression by LIN-1. In addition, we find that CKM mutation alters Mediator subunit requirements in vulva development: the mdt-23/sur-2 subunit, which is required for vulva development in wild-type worms, is dispensable for ectopic vulva formation in CKM mutants, which instead display hallmarks of unrestrained Mediator tail module activity. We propose a model whereby the CKM controls EGFR-Ras-ERK transcriptional output by corepressing LIN-1 and by fine tuning Mediator specificity, thus balancing transcriptional repression vs. activation in a critical developmental signaling pathway. Collectively, these data offer an explanation for CKM repression of EGFR signaling output and ectopic vulva formation and provide the first evidence of Mediator CKM-tail module subunit crosstalk in animals.KEYWORDS Mediator complex; CDK8; MED23; MED15; EGFR; Notch P RECISE regulation of transcription is required to execute developmental programs such as proliferation and cell fate determination. The Mediator complex ("Mediator") is a conserved eukaryotic transcriptional coregulator of RNA polymerase II (Pol II) transcription (Malik and Roeder 2010;Poss et al. 2013). Mediator consists of 30 subunits that assemble into four modules. "Core" Mediator consists of three of the four modules: the head and middle modules, which contact Pol II, and the tail module, which serves as a docking site for transcription factors. The fourth module, the dissociable cyclin dependent kinase 8 (CDK8) kinase module (CKM), interacts with transcription factors, core Mediator, chromatin, and the Pol II machinery to either repress or activate transcription (Malik and Roeder 2010;Nemet et al. 2014 transcription, tail and CKM subunits regulate specific transcriptional programs in animal development or physiology (Malik and Roeder 2010;Nemet et al. 2014). The CKM consists of enzymatic subunits CDK8 and cyclin C, and structural subunits MED12 and MED13 that tether the CKM to core Mediator (Tsai et al. 2013). C...

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Section: Discussionmentioning

confidence: 99%

Section: Cdk-8 Activity Is Kinase Dependentmentioning

confidence: 99%

Section: The Ckm Promotes Lin-1/ets Repressor Activitymentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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