title: Negative regulation of miR-145 by C/EBP-β through the Akt pathway in cancer cells.
abstract: MicroRNAs are master gene regulators that can also be under the control of transcriptional regulation. We have previously shown that miR-145 is a tumor suppressor capable of silencing c-Myc and the tumor suppressor p53 induces miR-145 by directly binding to the miR-145 promoter, demonstrating the role of miR-145 in p53-mediated c-Myc repression. However, little is known as to why miR-145 is often downregulated in tumors. In this study, we identify CCAAT/enhancer binding protein beta (C/EBP-β) as a negative regulator for miR-145 expression by direct interaction with the putative C/EBP-β binding site in the miR-145 promoter. In the wild-type p53 background, C/EBP-β counteracts the ability of p53 to induce miR-145. Moreover, C/EBP-β is able to suppress miR-145 in the mutant p53 background, suggesting the p53 independent regulation of miR-145. Of interest, both the large isoform (LAP-2) and the small isoform (LIP) of C/EBP-β can exert suppressive function for miR-145. Finally, we further show that, like serum starvation and PI3K inhibitor LY29, the antioxidant resveratrol suppresses pAkt and phosphorylation of C/EBP-β and at the same time, it induces miR-145. Together, these results suggest a miR-145 regulatory system involving the Akt and C/EBP-β, which may contribute to the downregulation of miR-145 in cancer cells.
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 62794, USA.
authors.forename: Mohit
authors.initials: M
authors.lastname: Sachdeva
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.forename: Julia
authors.initials: J
authors.lastname: Cao
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Lu
authors.forename: Yin-Yuan
authors.initials: YY
authors.lastname: Mo
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001665:Binding Sites; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000077185:Resveratrol; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D022782:CCAAT-Enhancer-Binding Protein-beta; D035683:MicroRNAs; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt; D000077185:Resveratrol