MAML1 Acts Cooperatively with EGR1 to Activate EGR1-Regulated Promoters: Implications for Nephrogenesis and the Development of Renal Cancer

Magnus L Hansson,Sadollah Mohammadi,Stefanie Behmer,Giulio Preta,Bengt Fadeel,Roland C Grafström,Rebecca Ceder,Annika E Wallberg,Alejandro H Corvalan

doi:10.1371/journal.pone.0046001

Magnus L Hansson, Sadollah Mohammadi + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0046001

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Journal: PloS one	Publication Date: Sep 27, 2012
Citations: 21	License type: CC BY 4.0

Affiliation: Karolinska Institutet

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.

Highlights

Mastermind-like 1 (MAML1) is the human homolog of Drosophila Mastermind, a neurogenic gene genetically linked to Notch function [1,2]
MAML1 regulates early growth response-1 (EGR1) mRNA and protein expression EGR1 protein stability has been reported to be stabilized by p300 acetylation, which results in the transactivation of survival genes [18]
As we previously found that MAML1 increases p300 autoacetylation, which enhanced the acetylation activity of p300 [11], we set out to investigate whether EGR1 expression levels could be elevated by MAML1

Summary

Introduction

Mastermind-like 1 (MAML1) is the human homolog of Drosophila Mastermind, a neurogenic gene genetically linked to Notch function [1,2]. MAML1 has been shown to function as a coactivator for transcription factors involved in a variety of Notch-independent signaling pathways, including myocyte enhancer factor 2C (MEF2C) [5], p53 [6] and beta-catenin [7], and the N-terminus of MAML1 is crucial for these interactions. These findings suggest that MAML1 functions as a coactivator in diverse cellular processes and may be a mediator of crosstalk between different signaling pathways. The MAML1 N-terminus is subject to SUMOylation, which represses the transcriptional activity of MAML1 [14]

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