title: JAZF1 promotes proliferation of C2C12 cells, but retards their myogenic differentiation through transcriptional repression of MEF2C and MRF4-Implications for the role of Jazf1 variants in oncogenesis and type 2 diabetes.
abstract: Single-nucleotide polymorphisms associated with type 2 diabetes (T2D) have been identified in Jazf1, which is also involved in the oncogenesis of endometrial stromal tumors. To understand how Jazf1 variants confer a risk of tumorigenesis and T2D, we explored the functional roles of JAZF1 and searched for JAZF1 target genes in myogenic C2C12 cells. Consistent with an increase of Jazf1 transcripts during myoblast proliferation and their decrease during myogenic differentiation in regenerating skeletal muscle, JAZF1 overexpression promoted cell proliferation, whereas it retarded myogenic differentiation. Examination of myogenic genes revealed that JAZF1 overexpression transcriptionally repressed MEF2C and MRF4 and their downstream genes. AMP deaminase1 (AMPD1) was identified as a candidate for JAZF1 target by gene array analysis. However, promoter assays of Ampd1 demonstrated that mutation of the putative binding site for the TR4/JAZF1 complex did not alleviate the repressive effects of JAZF1 on promoter activity. Instead, JAZF1-mediated repression of Ampd1 occurred through the MEF2-binding site and E-box within the Ampd1 proximal regulatory elements. Consistently, MEF2C and MRF4 expression enhanced Ampd1 promoter activity. AMPD1 overexpression and JAZF1 downregulation impaired AMPK phosphorylation, while JAZF1 overexpression also reduced it. Collectively, these results suggest that aberrant JAZF1 expression contributes to the oncogenesis and T2D pathogenesis.
authors.affiliation: Department of Anatomy and Cell Biology, Research Institute of Pharmaceutical Science, Faculty of Pharmacy, Musashino University, Nishitokyo, Tokyo 202-8585, Japan.
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Yuasa
authors.affiliation: Department of Anatomy and Cell Biology, Research Institute of Pharmaceutical Science, Faculty of Pharmacy, Musashino University, Nishitokyo, Tokyo 202-8585, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Aoki
authors.affiliation: Department of Anatomy and Cell Biology, Research Institute of Pharmaceutical Science, Faculty of Pharmacy, Musashino University, Nishitokyo, Tokyo 202-8585, Japan. Electronic address: hijikata@musashino-u.ac.jp.
authors.forename: Takao
authors.initials: T
authors.lastname: Hijikata
mesh_terms: D000659:AMP Deaminase / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D064326:MEF2 Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D024510:Muscle Development / Q000235:genetics*; D018485:Muscle Fibers, Skeletal / Q000166:cytology; D018006:Myogenic Regulatory Factors / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; C558308:JAZF1 protein, mouse; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C063403:myogenic factor 6; D000659:AMP Deaminase; C577245:AMPD1 protein, mouse
keywords: AMPD1; AMPK; JAZF1; MEF2C; MRF4; Type 2 diabetes