Capicua DNA-binding sites are general response elements for RTK signaling in Drosophila

  title={Capicua DNA-binding sites are general response elements for RTK signaling in Drosophila},
  author={Leiore Ajuria and Claudia Olmos Nieva and Clint J. Winkler and Dennis Kuo and N{\'u}ria Samper and Maria Jose Andreu and Aharon Helman and Sergio Gonz{\'a}lez-Crespo and Ze’ev Paroush and Albert J. Courey and Gerardo Jim{\'e}nez},
  pages={915 - 924}
RTK/Ras/MAPK signaling pathways play key functions in metazoan development, but how they control expression of downstream genes is not well understood. In Drosophila, it is generally assumed that most transcriptional responses to RTK signal activation depend on binding of Ets-family proteins to specific cis-acting sites in target enhancers. Here, we show that several Drosophila RTK pathways control expression of downstream genes through common octameric elements that are binding sites for the… 

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The Capicua repressor – a general sensor of RTK signaling in development and disease

Recent progress is highlighted in identifying the HMG-box protein Capicua (CIC) as a key sensor of RTK signaling in both Drosophila and mammals and increasing evidence supports the notion that this mechanism is conserved in mammals.

Origins of Context-Dependent Gene Repression by Capicua

Drosophila Cic relies on the Groucho (Gro) corepressor during its function in the early embryo, but not during other stages of development, suggesting that Cic-S and Gro coregulatory functions have facilitated the evolution of the complex transcriptional network regulated by Torso RTK signaling in modern fly embryos.

Capicua controls Toll/IL-1 signaling targets independently of RTK regulation

It is shown that Cic represses Toll/IL-1 signaling targets in Drosophila embryos independently of RTK control, revealing a mode of Cic regulation unrelated to the well-established RTK/Cic depression axis and implicate cooperative binding in conjunction with low-affinity binding sites as an important mechanism of enhancer regulation.

CIC (capicua transcriptional repressor)

CIC is a tissue-specific transcriptional repressor that is highly conserved between metazoan organisms and is required for the normal development of multiple adult structures and its dysfunction is associated with the neurodegenerative disorder spinocerebellar ataxia type 1, implicating CIC in neuronal cell development and/or homeostasis.

Context-dependent transcriptional interpretation of mitogen activated protein kinase signaling in the Drosophila embryo.

Data is presented suggesting that the asymmetric expression of tll is generated by a different mechanism, based on feedforward control and multiple enhancers of the tll gene, which correctly predicts how the wild-type expression pattern of tLL changes in mutants affecting the anterior, dorsoventral, and terminal patterning systems and some of their direct targets.

Lateral Gene Expression in Drosophila Early Embryos Is Supported by Grainyhead-Mediated Activation and Tiers of Dorsally-Localized Repression

It is shown that a short 12 base pair sequence present twice within the ind CRM is both necessary and sufficient to support transcriptional repression in dorsal regions of embryos and that TGF-β signaling acts to refine indCRM expression in an A-box independent manner in dorsal-most regions, suggesting that tiers of repression act in dorsal areas of the embryo.

Kinetics of gene derepression by ERK signaling

It is proposed that ERK-dependent relief of gene repression by Cic is a two-step process, in which fast reduction of repressor activity is followed by slower changes in nuclear localization and overall protein levels, which may be a common feature of systems in which ERK induces genes by relief of transcriptional repression.

A new mode of DNA binding distinguishes Capicua from other HMG-box factors and explains its mutation patterns in cancer

Capicua (CIC), an HMG-box transcriptional repressor involved in Ras/MAPK signaling and cancer progression, employs an additional distinct mode of DNA binding that enables selective recognition of its targets, and this binding mechanism operates throughout Drosophila development and in human cells, ensuring specific regulation of multiple CIC targets.

CIC Is a Mediator of the ERK1/2-DUSP6 Negative Feedback Loop




Multiple RTK pathways downregulate Groucho-mediated repression in Drosophila embryogenesis

It is proposed that phosphorylation of Groucho provides a widespread, long-term mechanism by which RTK signals control target gene expression and is essential for the transcriptional output of the pathway and for terminal cell specification.

The torso response element binds GAGA and NTF-1/Elf-1, and regulates tailless by relief of repression.

The data presented here support a model in which activation of the tor RTK at the poles of the embryos leads to inactivation of the repressor and therefore, to transcriptional activation (by activators present throughout the embryo) of the tll gene at the Poles of the embryo.

A MAPK docking site is critical for downregulation of Capicua by Torso and EGFR RTK signaling

The results are consistent with a model whereby Capicua is the main nuclear effector of the Torso pathway, but only one of different effectors responding to EGFR signaling, and differences in the modes ofCapicua downregulation by Torso and EGFR signaled, raising the possibility that such differences contribute to the tissue specificity of both signals.

Direct transcriptional control of the Dpp target omb by the DNA binding protein Brinker

The results identify Brk as a novel transcription factor antagonizing Dpp signalling by directly binding target genes and repressing their expression and identify a minimal 284 bp Dpp response element that is subject to Brinker (Brk) repression.

Spreading of a Corepressor Linked to Action of Long-Range Repressor Hairy

Observations suggest that long-range effects may be mediated by a “spreading” mechanism, modifying chromatin over extensive regions to inhibit transcription.

Dorsal-Mediated Repression Requires the Formation of a Multiprotein Repression Complex at the Ventral Silencer

The identified and purified an AT2 DNA binding activity in embryos and shown it to consist of cut and dead ringer gene products help clarify the mechanisms responsible for the regulatory specificity of transcription factors.

Differential in vivo requirements for oligomerization during Groucho‐mediated repression

The results show that homo‐oligomerization of Gro is not obligatory for its action in vivo, and that Gro represses transcription through more than one molecular mechanism.

Torso signalling regulates terminal patterning in Drosophila by antagonising Groucho-mediated repression.

It is shown that torso signalling permits terminal gap gene expression by antagonising Gro-mediated repression, and the corepressor Gro is employed in diverse developmental contexts and, probably, by a variety of DNA-binding repressors.