Structures of CSL, Notch and Mastermind proteins: piecing together an active transcription complex.

Notch signaling mediates communication between cells, and is essential for proper cell fate decisions in the developing embryo and the adult organism. Signaling initiates proteolytic release of the receptor Notch from the membrane, whereupon the intracellular portion of Notch (NotchIC) localizes to the nucleus and engages the DNA-binding transcription factor CSL. CSL is required for both repression and activation of Notch target genes, and is the focal point of a transcriptional switch, mediating interactions with transcriptional coregulators. Activation of transcription requires corepressor displacement from CSL by NotchIC and the recruitment of the transcriptional coactivator Mastermind to the complex. Several recently determined and exciting structures of CSL, NotchIC, and an active transcription complex composed of CSL, NotchIC and Mastermind have revealed new insights into transcriptional regulation in the Notch pathway.

[1]  D. Ganem,et al.  The lytic switch protein of KSHV activates gene expression via functional interaction with RBP-Jkappa (CSL), the target of the Notch signaling pathway. , 2002, Genes & development.

[2]  Iva Greenwald,et al.  LIN-12/Notch trafficking and regulation of DSL ligand activity during vulval induction in Caenorhabditis elegans , 2005, Development.

[3]  Jon C. Aster,et al.  Structural Basis for Cooperativity in Recruitment of MAML Coactivators to Notch Transcription Complexes , 2006, Cell.

[4]  Horst Hameister,et al.  SHARP is a novel component of the Notch/RBP‐Jκ signalling pathway , 2002 .

[5]  B. Lee,et al.  The interpretation of protein structures: estimation of static accessibility. , 1971, Journal of molecular biology.

[6]  D. Reinberg,et al.  The mammalian transcriptional repressor RBP (CBF1) targets TFIID and TFIIA to prevent activated transcription. , 1998, Genes & development.

[7]  E. Lai.  Keeping a good pathway down: transcriptional repression of Notch pathway target genes by CSL proteins , 2002, EMBO reports.

[8]  S. Artavanis-Tsakonas,et al.  Myc is a Notch1 transcriptional target and a requisite for Notch1-induced mammary tumorigenesis in mice. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[9]  T. Gridley.  Notch signaling and inherited disease syndromes. , 2003, Human molecular genetics.

[10]  W. Hendrickson,et al.  Crystal structure of the nuclear effector of Notch signaling, CSL, bound to DNA , 2004, The EMBO journal.

[11]  D. Barrick,et al.  Quantitative dissection of the Notch:CSL interaction: insights into the Notch-mediated transcriptional switch. , 2007, Journal of molecular biology.

[12]  Doug Barrick,et al.  An experimentally determined protein folding energy landscape. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[13]  S. Minoguchi,et al.  Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-Jκ/Su(H) , 1995, Current Biology.

[14]  K. Jones,et al.  Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex. , 2002, Genes & development.

[15]  Andrew P. Weng,et al.  Structural Requirements for Assembly of the CSL·Intracellular Notch1·Mastermind-like 1 Transcriptional Activation Complex* , 2003, Journal of Biological Chemistry.

[16]  S. Bray.  Notch signalling: a simple pathway becomes complex , 2006, Nature Reviews Molecular Cell Biology.

[17]  Larry Kedes,et al.  HES and HERP families: Multiple effectors of the notch signaling pathway , 2003, Journal of cellular physiology.

[18]  Rhett A. Kovall,et al.  Crystal Structure of the CSL-Notch-Mastermind Ternary Complex Bound to DNA , 2006, Cell.

[19]  V. Garg,et al.  Molecular genetics of aortic valve disease , 2006, Current opinion in cardiology.

[20]  T. Kadesch,et al.  Notch signaling: the demise of elegant simplicity. , 2004, Current opinion in genetics & development.

[21]  J. Bolívar,et al.  Epigenetic silencers and Notch collaborate to promote malignant tumours by Rb silencing , 2006, Nature.

[22]  L. D. Vales,et al.  Binding of C/EBP and RBP (CBF1) to Overlapping Sites Regulates Interleukin-6 Gene Expression* , 2002, The Journal of Biological Chemistry.

[23]  I. Greenwald,et al.  LIN-12/Notch signaling: lessons from worms and flies. , 1998, Genes & development.

[24]  Daniel C. Desrosiers,et al.  The ankyrin repeat as molecular architecture for protein recognition , 2004, Protein science : a publication of the Protein Society.

[25]  Christel Brou,et al.  Signalling downstream of activated mammalian Notch , 1995, Nature.

[26]  J. Hsieh,et al.  Masking of the CBF1/RBPJ kappa transcriptional repression domain by Epstein-Barr virus EBNA2. , 1995, Science.

[27]  G. Waksman,et al.  The crystal structure of a partial mouse Notch‐1 ankyrin domain: Repeats 4 through 7 preserve an ankyrin fold , 2005, Protein science : a publication of the Protein Society.

[28]  A. Capobianco,et al.  Characterization of a High-Molecular-Weight Notch Complex in the Nucleus of Notchic-Transformed RKE Cells and in a Human T-Cell Leukemia Cell Line , 2002, Molecular and Cellular Biology.

[29]  T. Honjo,et al.  Recognition sequence of a highly conserved DNA binding protein RBP-Jx , 1994 .

[30]  T. Honjo,et al.  Roles of the ankyrin repeats and C-terminal region of the mouse notch1 intracellular region. , 1998, Nucleic acids research.

[31]  M. Brodsky,et al.  A bacterial one-hybrid system for determining the DNA-binding specificity of transcription factors , 2005, Nature Biotechnology.

[32]  M. le Gall,et al.  Identification of Two Binding Regions for the Suppressor of Hairless Protein within the Intracellular Domain of Drosophila Notch* , 2004, Journal of Biological Chemistry.

[33]  D. Barrick,et al.  Studies of the ankyrin repeats of the Drosophila melanogaster Notch receptor. 1. Solution conformational and hydrodynamic properties. , 2001, Biochemistry.

[34]  W. Pear,et al.  Regulation of lymphoid development, differentiation, and function by the Notch pathway. , 2005, Annual review of immunology.

[35]  Jon C. Aster,et al.  Essential Roles for Ankyrin Repeat and Transactivation Domains in Induction of T-Cell Leukemia by Notch1 , 2000, Molecular and Cellular Biology.

[36]  K. Jones,et al.  Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. , 2004, Molecular cell.

[37]  G. Kleywegt.  Use of non-crystallographic symmetry in protein structure refinement. , 1996, Acta crystallographica. Section D, Biological crystallography.

[38]  F. Schweisguth,et al.  The roles of receptor and ligand endocytosis in regulating Notch signaling , 2005, Development.

[39]  J. Aster,et al.  c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. , 2006, Genes & development.

[40]  U. Lendahl,et al.  p300 and PCAF Act Cooperatively To Mediate Transcriptional Activation from Chromatin Templates by Notch Intracellular Domains In Vitro , 2002, Molecular and Cellular Biology.

[41]  Raphael Kopan,et al.  Anchoring notch genetics and biochemistry; structural analysis of the ankyrin domain sheds light on existing data. , 2004, Molecular cell.

[42]  Sean J. Morrison,et al.  Asymmetric and symmetric stem-cell divisions in development and cancer , 2006, Nature.

[43]  M. Dominguez.  Interplay between Notch signaling and epigenetic silencers in cancer. , 2006, Cancer research.

[44]  Raphael Kopan,et al.  Notch signaling: from the outside in. , 2000, Developmental biology.

[45]  T. Honjo,et al.  Functional Interaction between the Mouse Notch1 Intracellular Region and Histone Acetyltransferases PCAF and GCN5* , 2000, The Journal of Biological Chemistry.

[46]  M. Dettke,et al.  Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia. , 2002, Blood.

[47]  J. Hsieh,et al.  SKIP, a CBF1-Associated Protein, Interacts with the Ankyrin Repeat Domain of NotchIC To Facilitate NotchIC Function , 2000, Molecular and Cellular Biology.

[48]  A. Karsan,et al.  Recent insights into the role of Notch signaling in tumorigenesis. , 2006, Blood.

[49]  Dimitri Y Chirgadze,et al.  High-resolution crystal structure of the human Notch 1 ankyrin domain. , 2005, The Biochemical journal.

[50]  S. Barolo,et al.  Default repression and Notch signaling: Hairless acts as an adaptor to recruit the corepressors Groucho and dCtBP to Suppressor of Hairless. , 2002, Genes & development.

[51]  A. Capobianco,et al.  Induction of Cyclin D1 Transcription and CDK2 Activity by Notchic: Implication for Cell Cycle Disruption in Transformation by Notchic , 2001, Molecular and Cellular Biology.

[52]  R. Evans,et al.  A histone deacetylase corepressor complex regulates the Notch signal transduction pathway. , 1998, Genes & development.

[53]  J. Hsieh,et al.  CIR, a corepressor linking the DNA binding factor CBF1 to the histone deacetylase complex. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[54]  G. Stormo,et al.  Target Selectivity of Vertebrate Notch Proteins , 2006, Journal of Biological Chemistry.

[55]  J. Aster,et al.  Identification of a Conserved Negative Regulatory Sequence That Influences the Leukemogenic Activity of NOTCH1 , 2006, Molecular and Cellular Biology.

[56]  S. Minoguchi,et al.  Involvement of RBP-J in biological functions of mouse Notch1 and its derivatives. , 1997, Development.

[57]  Doug Barrick,et al.  Structure and stability of the ankyrin domain of the Drosophila Notch receptor , 2003, Protein science : a publication of the Protein Society.

[58]  J. Hsieh,et al.  A Role for SKIP in EBNA2 Activation of CBF1-Repressed Promoters , 2000, Journal of Virology.