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

Jenkins, Robert Hywel ORCID: https://orcid.org/0000-0001-8500-9044, Martin, John, Phillips, Aled Owain ORCID: https://orcid.org/0000-0001-9744-7113, Bowen, Timothy ORCID: https://orcid.org/0000-0001-6050-0435 and Fraser, Donald James ORCID: https://orcid.org/0000-0003-0102-9342 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:	Schools > Medicine Research Institutes & Centres > 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:	09 Jun 2023 06:45
URI:	https://orca.cardiff.ac.uk/id/eprint/41915

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