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

<p>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.</p><p>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.</p><p>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.</p><h3>List of scientific papers</h3><p>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. <br><a href="https://doi.org/10.1093/nar/gkp163">https://doi.org/10.1093/nar/gkp163</a><br><br> </p><p>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. <br><a href="https://doi.org/10.1093/nar/gkp724">https://doi.org/10.1093/nar/gkp724</a><br><br> </p><p>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. <br><a href="https://doi.org/10.1096/fj.09-149401">https://doi.org/10.1096/fj.09-149401</a><br><br> </p><p>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]</p>