CSL-Associated Corepressor and Coactivator Complexes

Oswald, Franz; Kovall, Rhett A.

doi:10.1007/978-3-319-89512-3_14

Franz Oswald⁸ &
Rhett A. Kovall⁹

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1066))

3614 Accesses
21 Citations

Abstract

The highly conserved Notch signal transduction pathway orchestrates fundamental cellular processes including, differentiation, proliferation, and apoptosis during embryonic development and in the adult organism. Dysregulated Notch signaling underlies the etiology of a variety of human diseases, such as certain types of cancers, developmental disorders and cardiovascular disease. Ligand binding induces proteolytic cleavage of the Notch receptor and nuclear translocation of the Notch intracellular domain (NICD), which forms a ternary complex with the transcription factor CSL and the coactivator MAML to upregulate transcription of Notch target genes. The DNA-binding protein CSL is the centrepiece of transcriptional regulation in the Notch pathway, acting as a molecular hub for interactions with either corepressors or coactivators to repress or activate, respectively, transcription. Here we review previous structure-function studies of CSL-associated coregulator complexes and discuss the molecular insights gleaned from this research. We discuss the functional consequences of both activating and repressing binding partners using the same interaction platforms on CSL. We also emphasize that although there has been a significant uptick in structural information over the past decade, it is still under debate how the molecular switch from repression to activation mediated by CSL occurs at Notch target genes and whether it will be possible to manipulate these transcription complexes therapeutically in the future.

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Abbreviations

CBF1:: C-promoter Binding Factor 1
LAG-1:: abnormal cell LINeage-12 (Lin-12) And abnormal Germ line proliferation phenotype-1 (Glp-1)
RBP-J:: Recombination Signal-Binding Protein for immunoglobin kappa J region
Su(H):: Suppressor of Hairless
CBP/CREBBP:: C-Adenosine Mono Phosphate Responsive Element (cAMP-RE)-Binding protein (CREB)-Binding Protein; KAT3A
EP300:: E1A Binding Protein P300, KAT3B
PCAF:: P300/CBP-Associated Factor; KAT2B
GCN5:: General Control Of AmiNo Acid Synthesis Protein 5-Like 2; KAT2A
CDK8:: Cyclin-Dependent Kinase 8
SCF:: S-Phase Kinase Associated Protein1/Cullin/F-Box Protein
SEL10:: Suppressor and/or Enhancer of abnormal cell LINeage-12 (Lin-12)-10
FBWX7:: F-Box and WD Repeat Domain containing 7
SIRT-1:: Sirtuin-1
CARM1:: Coactivator-Associated Arginine Methyltransferase1
PRMT4:: Protein Arginine N-MethylTransferase 4
CTBP:: C-Terminal Binding Protein
CTIP:: CTBP Interacting Protein
KYOT2/FHL1:: Four and a Half LIM domains 1
NCoR:: Nuclear Receptor CoRepressor
SMRT:: Silencing Mediator For Retinoid And Thyroid Hormone Receptors
SHARP:: SMRT/HDAC1-Associated Repressor Protein
SPEN:: SPlit ENds family transcriptional repressor
LID:: Little Imaginal Disks
KDM5A:: Lysine(K) Demethylase 5A
CIR:: Corepressor Interacting with RBPJ
SKIP:: Sloan-KetterIng-retroviral oncogene (SKI) -Interacting Protein
L3MBTL3:: Lethal(3)Malignant Brain Tumor-Like Protein 3
RITA1:: RBPJ Interacting and Tubulin Associated 1
EBNA2:: Epstein-Barr Virus Nuclear Antigen 2
NFAT:: Nuclear Factor of Activated T-cells
NF-κB1:: Nuclear Factor κB1
POFUT1:: Protein O-Fucosyltransferase 1
Fringe:: Beta-1,3-N-Acetylglucosaminyltransferase

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Acknowledgments

We want to thank Bernd Baumann for critical reading of the manuscript. Research in the F.O. laboratory is supported by the DFG (SFB1074/A3) and the BMBF (Federal Ministry of Education and Research, research nucleus SyStAR). Research in the R.A.K. laboratory is supported by the NIH (CA178974), NSF (MCB-1715822), and the Bankhead-Coley Cancer Research Program.

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University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine I, University of Ulm, Ulm, Germany
Franz Oswald
Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
Rhett A. Kovall

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Franz Oswald
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Correspondence to Franz Oswald or Rhett A. Kovall .

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Institute of Biochemistry, University of Giessen, Giessen, Germany
Tilman Borggrefe
Institute of Biochemistry, University of Giessen, Giessen, Germany
Benedetto Daniele Giaimo

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Oswald, F., Kovall, R.A. (2018). CSL-Associated Corepressor and Coactivator Complexes. In: Borggrefe, T., Giaimo, B. (eds) Molecular Mechanisms of Notch Signaling. Advances in Experimental Medicine and Biology, vol 1066. Springer, Cham. https://doi.org/10.1007/978-3-319-89512-3_14

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DOI: https://doi.org/10.1007/978-3-319-89512-3_14
Published: 19 July 2018
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-89511-6
Online ISBN: 978-3-319-89512-3
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