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Gene regulation mechanisms by the transcriptional coregulator mastermind-like 1

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posted on 2024-09-03, 04:55 authored by Mariana Saint Just Ribeiro

MAML1 was first identified as a coactivator for Notch receptors, but later it was also found to function as a coactivator for several other activators, including p53, beta-catenin, and MEF2C. MAML1 is critical for Notch signalling and has been shown to act cooperatively with the histone acetyltransferase (HAT) p300 in transcription that is mediated by the Notch intracellular domain (Notch IC). Furthermore, it has been shown that the MAML1 protein is crucial for the p300-mediated acetylation of histones in chromatin templates.

We have investigated the molecular interplay between MAML1 and p300 during Notch-mediated transcription. We reported that the N-terminal domain of MAML1 interacts directly with the C/H3 domain of p300 and with histones, and that the p300-MAML1 complex specifically acetylates the tails of histones H3 and H4. Furthermore, we showed that MAML1 is acetylated by p300, and identified conserved lysines in the MAML1 N-terminus as the target for p300 acetylation. We found that MAML1 contains a proline repeat domain that is important for its activity, for p300-mediated acetylation, and for interaction with p300. Next, we investigated how MAML1 can influence the activity of p300. We found that MAML1 enhances p300 autoacetylation, which requires the HAT and C/H3 domains of p300. MAML1 directly enhances the HAT activity of p300 and this correlates with the translocation of MAML1, p300, and acetylated histones to nuclear bodies.

We found that MAML1 is phosphorylated in vivo at serine and threonine residues. We then investigated whether MAML1 could be phosphorylated by GSK3beta, which is a kinase known to phosphorylate Notch IC in the nucleus. We found that GSK3beta phosphorylates the N-terminus of MAML1, and that inhibition of GSK3beta abolishes the GSK3beta-dependent phosphorylation of MAML1 in vitro. Furthermore, we found that GSK3beta interacts with the N-terminus of MAML1 and targets it for downregulation. We also showed that GSK3beta must be active in order to repress MAML1. The transcriptional activity of MAML1 and the global levels of histone acetylation are upregulated when GSK3beta is inhibited. Finally, MAML1 translocates GSK3beta to nuclear bodies, in a process that requires the full-length MAML1 protein.

List of scientific papers

I. Saint Just Ribeiro M, Hansson ML, Wallberg AE (2007). A proline repeat domain in the Notch co-activator MAML1 is important for the p300-mediated acetylation of MAML1. Biochem J. 404(2): 289-98
https://pubmed.ncbi.nlm.nih.gov/17300219

II. Hansson ML, Popko-Scibor AE, Saint Just Ribeiro M, Dancy BM, Lindberg MJ, Cole PA, Wallberg AE (2009). The transcriptional coactivator MAML1 regulates p300 autoacetylation and HAT activity. Nucleic Acids Res. Mar 25: Epub ahead of print
https://pubmed.ncbi.nlm.nih.gov/19304754

III. Saint Just Ribeiro M, Hansson ML, Lindberg MJ, Popko-Scibor AE, Wallberg AE (2009). GSK3beta is a negative regulator of the transcriptional coactivator MAML1. [Manuscript]

History

Defence date

2009-04-17

Department

  • Department of Medicine, Huddinge

Publication year

2009

Thesis type

  • Doctoral thesis

ISBN

978-91-7409-411-4

Number of supporting papers

3

Language

  • eng

Original publication date

2009-03-27

Author name in thesis

Saint Just Ribeiro, Mariana

Original department name

Biosciences and Nutrition

Place of publication

Stockholm

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