title: MAML1 acts cooperatively with EGR1 to activate EGR1-regulated promoters: implications for nephrogenesis and the development of renal cancer.
abstract: Mastermind-like 1 (MAML1) is a transcriptional coregulator of activators in various signaling pathways, such as Notch, p53, myocyte enhancer factor 2C (MEF2C) and beta-catenin. In earlier studies, we demonstrated that MAML1 enhanced p300 acetyltransferase activity, which increased the acetylation of Notch by p300. In this study, we show that MAML1 strongly induced acetylation of the transcription factor early growth response-1 (EGR1) by p300, and increased EGR1 protein expression in embryonic kidney cells. EGR1 mRNA transcripts were also upregulated in the presence of MAML1. We show that MAML1 physically interacted with, and acted cooperatively with EGR1 to increase transcriptional activity of the EGR1 and p300 promoters, which both contain EGR1 binding sites. Bioinformatics assessment revealed a correlation between p300, EGR1 and MAML1 copy number and mRNA alterations in renal clear cell carcinoma and p300, EGR1 and MAML1 gene alterations were associated with increased overall survival. Our findings suggest MAML1 may be a component of the transcriptional networks which regulate EGR1 target genes during nephrogenesis and could also have implications for the development of renal cell carcinoma.
authors.affiliation: Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Magnus L
authors.initials: ML
authors.lastname: Hansson
authors.forename: Stefanie
authors.initials: S
authors.lastname: Behmer
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ceder
authors.forename: Sadollah
authors.initials: S
authors.lastname: Mohammadi
authors.forename: Giulio
authors.initials: G
authors.lastname: Preta
authors.forename: Roland C
authors.initials: RC
authors.lastname: Grafström
authors.forename: Bengt
authors.initials: B
authors.lastname: Fadeel
authors.forename: Annika E
authors.initials: AE
authors.lastname: Wallberg
mesh_terms: D000107:Acetylation; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000235:genetics* / Q000378:metabolism; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D025941:Protein Interaction Mapping; D012333:RNA, Messenger / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; D012333:RNA, Messenger; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C430872:MAML1 protein, human