MAML1, a human homologue of Drosophila Mastermind, is a transcriptional co-activator for NOTCH receptors

Abstract

Notch receptors are involved in cell-fate determination in organisms as diverse as flies, frogs and humans1. 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 nucleus2, and interacts directly with the DNA-binding protein Suppressor of hairless (Su(H)) in flies, or recombination signal binding protein Jκ (RBP-Jκ) in mammals3, to activate gene transcription4. 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 Drosophila5,6,7,8. 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-Jκ, 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.

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Figure 1: MAML1 structure and expression.
Figure 2: MAML1 subcellular localization and its colocalization with PML and ICN/RBPJκ in nuclear bodies.
Figure 3: Detection of a ternary complex of MAML1, ICN and RBP-Jκ in vivo.
Figure 4: MAML1 binds directly to the anykyrin repeats of NOTCH.
Figure 5: MAML1 cooperates with NOTCH to activate the HES1 promoter.
Figure 6: MAML1 mutants lacking the NOTCH-binding site or the transcriptional activation domain block ligand-induced signalling.

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Acknowledgements

We thank K. Kobayashi and V. Patriubavicius for technical assistance, and B. Bernstein and Y. Nam for design and purification of the ANK and RAM-ANK fragments of NOTCH1. Supported by NIH grants CA09362 (L.W.), CA82308 (J.CA.), HL-61001 (S.C.B.), and CA36167, CA66996 and DK50654 (J.D.G.); and Barr-Weaver Funds from Dana-Farber Cancer Institute. S.C.B. is a Pew Scholar in the Biomedical Sciences. S.A.-T is supported by the Howard Hughes Medical Institute

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Correspondence to James D. Griffin.

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Wu, L., Aster, J., Blacklow, S. et al. MAML1, a human homologue of Drosophila Mastermind, is a transcriptional co-activator for NOTCH receptors. Nat Genet 26, 484–489 (2000). https://doi.org/10.1038/82644

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