Molecular mechanisms of the transcriptional co-activator mastermind-like 1

Gene regulation is a complex process that requires several types of proteins, including chromatin-modifying enzymes, transcription factors, co-activators and co-repressors. We have investigated the molecular mechanisms underlying the action of the co-activator protein MAML1, which was first identified as a transcriptional co-activator for Notch receptors. Recently, MAML1 has been shown to function as a co-activator for other transcription factors, including β-catenin, p53 and MEF2C. We found that the co-activator function of MAML1 can be repressed by two different post-translational modification mechanisms; viz. phosphorylation by GSK3β and SUMOylation. The GSK3β kinase is reported to phosphorylate Notch1 and Notch2, and the GSK3β binding and phosphorylation sites have been mapped to the N-terminus of MAML1. We showed that GSK3β inhibits MAML1-mediated transcription, and that the inhibition is dependent on active GSK3β. Moreover, immunofluorescence experiments showed that Notch1, MAML1 and GSK3β are co-localized in nuclear bodies.

We found that MAML1 can be SUMOylated at two conserved SUMOylation consensus motifs located in the N-terminus. The SUMO-deficient MAML1 mutant was a much more potent co-activator than the wild type. Moreover, SUMOylation of MAML1 resulted in an increased recruitment of the co-repressor HDAC7. Therefore, we suggest that SUMOylation of MAML1 is a mechanism for suppression of the transcriptional activity of MAML1.

Earlier, we reported that the histone acetyltransferase p300 acetylates MAML1. Here, we describe additional links between the general co-activator p300 and MAML1. First, we show that MAML1 enhances the autoacetylation of p300 in vitro and in cultured cells, which caused increased acetylation of the p300 substrates histone H3/H4 and the transcription factor Egr1. Second, we found that MAML1 and Egr1 physically interact, and synergistically increase the expression of promoters regulated by Egr1, including the p300 promoter.

List of scientific papers

I. Hansson ML, Popko-Scibor AE*, Saint Just Ribeiro M*, Dancy BM, Lindberg MJ, Cole PA and Wallberg AE. (2009) The transcriptional coactivator MAML1 regulates p300 autoacetylation and HAT activity. Nucleic Acids Res. 37(9):2996-3006.
https://doi.org/10.1093/nar/gkp163

II. Saint Just Ribeiro M*, Hansson ML*, Lindberg MJ, Popko-Scibor AE and Wallberg, AE. (2009) GSK3beta is a negative regulator of the transcriptional coactivator MAML1. Nucleic Acids Res. 37(20):6691-700.
https://doi.org/10.1093/nar/gkp724

III. Lindberg MJ, Popko-Scibor AE, Hansson ML and Wallberg AE. (2010) SUMO modification regulates the transcriptional activity of MAML1. FASEB J. 24(7):2396-404.
https://doi.org/10.1096/fj.09-149401

IV. Hansson ML, Behmer S and Wallberg AE. (2010) MAML1 and Early growth response-1 act cooperatively to increase expression of promoters regulated by EGR1. [Manuscript]