MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors.
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.
Wu
L
L
Department of Adult Oncology, Dana-Farber Cancer Institute and Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Aster
J C
JC
Blacklow
S C
SC
Lake
R
R
Artavanis-Tsakonas
S
S
Griffin
J D
JD
D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D004268:DNA-Binding Proteins; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins; D017344:Genes, Insect; D006801:Humans; D019476:Insect Proteins / Q000235:genetics* / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism*; D051880:Receptors, Notch; D013045:Species Specificity; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors; D014162:Transfection
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D019476:Insect Proteins; C430872:MAML1 protein, human; D008565:Membrane Proteins; C497759:N protein, Drosophila; D009687:Nuclear Proteins; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D015534:Trans-Activators; D014157:Transcription Factors; C085316:mam protein, Drosophila