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CSL-Associated Corepressor and Coactivator Complexes

  • Franz Oswald
  • Rhett A. Kovall
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1066)

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.

Keywords

Notch CSL Structure analysis RAM domain Coactivator complex Corepressor complex DNA-binding Transcription 

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

Notes

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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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine IUniversity of UlmUlmGermany
  2. 2.Department of Molecular Genetics, Biochemistry and MicrobiologyUniversity of Cincinnati College of MedicineCincinnatiUSA

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