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PMID:11101851

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Citation

Wu, L, Aster, JC, Blacklow, SC, Lake, R, Artavanis-Tsakonas, S and Griffin, JD (2000) MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Nat. Genet. 26:484-9

Abstract

Notch receptors are involved in cell-fate determination in organisms as diverse as flies, frogs and humans. In Drosophila melanogaster , loss-of-function mutations of Notch produce a 'neurogenic' phenotype in which cells destined to become epidermis switch fate and differentiate to neural cells. Upon ligand activation, the intracellular domain of Notch (ICN) translocates to the nucleus, and interacts directly with the DNA-binding protein Suppressor of hairless (Su(H)) in flies, or recombination signal binding protein Jkappa (RBP-Jkappa) in mammals, to activate gene transcription. But the precise mechanisms of Notch-induced gene expression are not completely understood. The gene mastermind has been identified in multiple genetic screens for modifiers of Notch mutations in Drosophila. Here we clone MAML1, a human homologue of the Drosophila gene Mastermind, and show that it encodes a protein of 130 kD localizing to nuclear bodies. MAML1 binds to the ankyrin repeat domain of all four mammalian NOTCH receptors, forms a DNA-binding complex with ICN and RBP-Jkappa, and amplifies NOTCH-induced transcription of HES1. These studies provide a molecular mechanism to explain the genetic links between mastermind and Notch in Drosophila and indicate that MAML1 functions as a transcriptional co-activator for NOTCH signalling.

Links

PubMed Online version:10.1038/82644

Keywords

3T3 Cells; Animals; COS Cells; DNA-Binding Proteins; Drosophila/genetics; Drosophila Proteins; Genes, Insect; Humans; Insect Proteins/genetics; Insect Proteins/metabolism; Membrane Proteins/genetics; Membrane Proteins/metabolism; Mice; Molecular Sequence Data; Mutation; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Receptors, Cell Surface/genetics; Receptors, Cell Surface/metabolism; Receptors, Notch; Species Specificity; Trans-Activators/genetics; Trans-Activators/metabolism; Transcription Factors; Transfection

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:NOTC1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q92585

F

Seeded From UniProt

complete

HUMAN:NOTC2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q92585

F

Seeded From UniProt

complete

HUMAN:MAML1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q04721

F

Seeded From UniProt

complete

HUMAN:MAML1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9UM47

F

Seeded From UniProt

complete

HUMAN:MAML1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99466

F

Seeded From UniProt

complete

HUMAN:MAML1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P46531

F

Seeded From UniProt

complete

HUMAN:MAML1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:MAML1

involved_in

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MAML1

enables

GO:0003713: transcription coactivator activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:MAML1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NOTC4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q92585

F

Seeded From UniProt

complete

HUMAN:NOTC3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q92585

F

Seeded From UniProt

complete


See also

References

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