SUMOylation negatively regulates transcriptional and oncogenic activities of MafA

• Published in: Genes to cells : devoted to molecular & cellular mechanisms Vol. 15; no. 9; pp. 971 - 982
• Main Authors: Kanai, Kenichi, Reza, Hasan Mahmud, Kamitani, Akiyo, Hamazaki, Yuri, Han, Song-iee, Yasuda, Kunio, Kataoka, Kohsuke
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.09.2010; Blackwell Publishing Ltd
• Subjects: Animals; Beta cells; c-Maf protein; Cell Line; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Chick Embryo; Colonies; Crystallin; delta-Crystallins - genetics; Differentiation; Electroporation; Embryo fibroblasts; Embryos; Fibroblasts - cytology; Fibroblasts - metabolism; Gene Expression Regulation, Developmental; HeLa Cells; Humans; Insulin; Lysine; Lysine - genetics; Lysine - metabolism; Maf protein; Maf Transcription Factors, Large - genetics; Maf Transcription Factors, Large - metabolism; MafA protein; MafB Transcription Factor - genetics; MafB Transcription Factor - metabolism; Mice; Multiple myeloma; Mutation; NIH 3T3 Cells; Pancreas; Phosphorylation; Post-translation; Promoters; Serine; Small Ubiquitin-Related Modifier Proteins - genetics; Small Ubiquitin-Related Modifier Proteins - metabolism; SUMO protein; Sumoylation; Threonine; Transcription; Transcription factors; Transcription, Genetic - genetics; Transfection; Transformation
• ISSN: 1356-9597; 1365-2443
• DOI: 10.1111/j.1365-2443.2010.01431.x

Dysregulated expression of Maf proteins (namely c-Maf, MafA and MafB) leads to multiple myeloma in humans and oncogenic transformation of chicken embryonic fibroblasts. Maf proteins are transcriptional activators of tissue-specific gene expression and regulators of cell differentiation. For example, MafA is a critical regulator of crystallin genes and the lens differentiation program in chickens. In mammals, MafA is essential for the development of mature insulin-producing β-cells of pancreas. It has been shown that MafA protein stability is regulated by phosphorylations at multiple serine and threonine residues. Here, we report that Maf proteins are also post-translationally modified by small ubiquitin-like modifier (SUMO) proteins at a conserved lysine residue in the amino-terminal transactivator domain. A SUMOylation-deficient mutant of MafA (K32R) was more potent than wild-type MafA in transactivating luciferase reporter construct driven by αA-crystallin or insulin gene promoter. In ovo electroporation into developing chicken embryo showed that the K32R mutant induced ectopic δ-crystallin gene expression more efficiently than the wild-type MafA. We also demonstrated that the K32R mutant had enhanced ability to induce colony formation of a chicken fibroblast cell line DF-1. Therefore, SUMOylation is a functional post-translational modification of MafA that negatively regulates its transcriptional and transforming activities.