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Transforming growth factor β1 represses proximal tubular cell microRNA-192 expression through decreased hepatocyte nuclear factor DNA binding

Jenkins, Robert Hywel, Martin, John, Phillips, Aled Owain, Bowen, Timothy and Fraser, Donald James 2012. Transforming growth factor β1 represses proximal tubular cell microRNA-192 expression through decreased hepatocyte nuclear factor DNA binding. Biochemical Journal 443 (2) , pp. 407-416. 10.1042/BJ20111861

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Abstract

miR (microRNA)-192 plays key roles in renal pathological and physiological responses, by repressing targets including Zeb1, Zeb2 and Wnk1. In the present study, we have assessed the regulation of miR-192 expression. We found that TGF-β1 (transforming growth factor β1) down-regulates miR-192 and miR-194, co-transcribed in the shared precursor pri-miR (primary miR transcript)-192/194. Luciferase reporter analysis showed constitutive promoter activity within nucleotides +21 to −223. We identified HNF (hepatocyte nuclear factor) and p53 binding sites within this region that were required for constitutive promoter activity, which was decreased by TGF-β1 through an Alk5-dependent mechanism. TGF-β1 treatment decreased HNF binding to the miR-194-2/192 promoter, whereas knockdown of HNF-1 inhibited mature miR-192 and miR-194 expression. miR-192, miR-194 and HNF expression were restricted to a defined subset of human tissues including kidney, small intestine, colon and liver. Our results from the present study identify co-ordinated regulation of miR-192 and miR-194, with binding of HNF and p53 transcription factors necessary for activation of transcription, and TGF-β1-mediated repression through decreased HNF binding to its cognate promoter element.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: hepatocyte nuclear factor (HNF); kidney; microRNA; p53; promoter; transforming growth factor β (TGF-β)
Publisher: Biochemical Society
ISSN: 0264-6021
Last Modified: 11 Sep 2019 21:18
URI: http://orca.cf.ac.uk/id/eprint/41915

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