SUMOylation negatively regulates transcriptional and oncogenic activities of MafA.
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 beta-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 alphaA-crystallin or insulin gene promoter. In ovo electroporation into developing chicken embryo showed that the K32R mutant induced ectopic delta-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.
Kanai
Kenichi
K
Nara Institute of Science and Technology, Takayama-cho, Ikoma, Japan.
Reza
Hasan Mahmud
HM
Kamitani
Akiyo
A
Hamazaki
Yuri
Y
Han
Song-iee
SI
Yasuda
Kunio
K
Kataoka
Kohsuke
K
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002642:Chick Embryo; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D051473:Maf Transcription Factors, Large / Q000235:genetics* / Q000378:metabolism; D051258:MafB Transcription Factor / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism; D058207:Sumoylation; D014158:Transcription, Genetic / Q000235:genetics*; D014162:Transfection; D038207:delta-Crystallins / Q000235:genetics
D051473:Maf Transcription Factors, Large; D051258:MafB Transcription Factor; C485160:Mafa protein, mouse; D025841:Small Ubiquitin-Related Modifier Proteins; D038207:delta-Crystallins; D008239:Lysine