A histone deacetylase corepressor complex regulates the Notch signal transduction pathway.
The Delta-Notch signal transduction pathway has widespread roles in animal development in which it appears to control cell fate. CBF1/RBP-Jkappa, the mammalian homolog of Drosophila Suppressor of Hairless [Su(H)], switches from a transcriptional repressor to an activator upon Notch activation. The mechanism whereby Notch regulates this switch is not clear. In this report we show that prior to induction CBF1/RBP-Jkappa interacts with a corepressor complex containing SMRT (silencing mediator of retinoid and thyroid hormone receptors) and the histone deacetylase HDAC-1. This complex binds via the CBF1 repression domain, and mutants defective in repression fail to interact with the complex. Activation by Notch disrupts the formation of the repressor complex, thus establishing a molecular basis for the Notch switch. Finally, ESR-1, a Xenopus gene activated by Notch and X-Su(H), is induced in animal caps treated with TSA, an inhibitor of HDAC-1. The functional role for the SMRT/HDAC-1 complex in CBF1/RBP-Jkappa regulation reveals a novel genetic switch in which extracellular ligands control the status of critical nuclear cofactor complexes.
Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, California 92037 USA.
H Y
HY
Kao
P
P
Ordentlich
N
N
Koyano-Nakagawa
Z
Z
Tang
M
M
Downes
C R
CR
Kintner
R M
RM
Evans
T
T
Kadesch
D016475:3T3 Cells; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology; D009154:Mutation; D009687:Nuclear Proteins; D056985:Nuclear Receptor Co-Repressor 2; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors; D014162:Transfection; D014981:Xenopus
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D008565:Membrane Proteins; C497759:N protein, Drosophila; C539131:Ncor2 protein, mouse; C497762:Notch1 protein, mouse; D009687:Nuclear Proteins; D056985:Nuclear Receptor Co-Repressor 2; C497571:Rbpj protein, mouse; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D012097:Repressor Proteins; D014157:Transcription Factors; D006655:Histone Deacetylases