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Tissue-specific differences in the regulation of KIBRA gene expression involve transcription factor TCF7L2 and a complex alternative promoter system

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Abstract

KIBRA has been described as a key regulator of the Hippo signaling pathway, regulating organ size control, cell contact inhibition, cell growth, as well as tumorigenesis and cystogenesis. Since there is scarce information on KIBRA gene expression regulation, we analyzed the molecular basis of tissue-specific KIBRA expression in human kidney epithelial (IHKE, HPCT) and neuroblastoma (SH-SY5Y, SK-SN-SH) cells. We detected four novel and differentially used transcription start sites, two of which positioned in the first intron, generating two novel alternative exons. We identified one constitutively active core promoter (P1a) and three alternative promoters (P1b, P2, and P3), which were exclusively active in kidney cells. Transcription factor 7-like 2 (TCF7L2) selectively activated KIBRA at P1a, P2, and P3 in kidney cells. The two genetic variants −580C>T (p < 0.05) and −1691C>T (p < 0.01) significantly affected the transcriptional activity of the KIBRA core promoter. We propose a novel functional structure of the KIBRA gene and provide detailed insight into molecular cell type-specific KIBRA transcriptional regulation by TCF7L2, the Yes-associated protein 1 and TEA domain family member. Our findings provide a potential basis for future studies on malfunctioning KIBRA regulation in pathophysiological conditions such as cancer development.

Key message

  • KIBRA expression is regulated by three independent, cell type-specific promoters

  • Two novel TSS were located within intron one resulting in two alternative exons

  • TSS utilization is cell type-specific

  • TCF7L2, YAP1, and TEAD are involved in the differential KIBRA expression regulation

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Acknowledgments

We are grateful to Peter Kleine-Katthöfer (St. Franziskus-Hospital Münster) and Peter Baumgart (Clemenshospital GmbH Münster), supplying genomic DNA for the MolProMD Study. IHKE and HPCT cells were a kind gift of Eberhardt Schlatter, Department of Experimental Nephrology, University Hospital Münster and Ulrich Hopfer, Department of Physiology and Biophysics, Case Western Reserve University School of Medicine. Human brain cortex tissue was provided by Tanja Kuhlmann, Institute of Neuropathology, University Hospital Münster. We thank Birgit Orlowski and Alois Rötrige for excellent technical assistance. Eva Brand is supported by a Heisenberg professorship from the Deutsche Forschungsgemeinschaft (Br1589/8-2). This study was also supported by a grant from the European Union-Project Network of Excellence, FP6-2005-LIFESCIHEALTH-6, Integrating Genomics, Clinical Research and Care in Hypertension, InGenious HyperCare (proposal no. 037093 to Eva Brand and Stefan-Martin Brand) and an ICT in the FP7-ICT-2007-2, project number 224635, VPH2-Virtual Pathological Heart of the Virtual Physiological Human (supported Boris Schmitz), to Stefan-Martin Brand, formerly Stefan-Martin Brand­Herrmann/Stefan-Martin Herrmann.

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None declared.

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Authors and Affiliations

  1. Internal Medicine D, Nephrology, Hypertension and Rheumatology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany

    Katrin Guske, Boris Schmitz, Michael Schelleckes, Kerstin Duning, Joachim Kremerskothen, Hermann J. Pavenstädt & Eva Brand

  2. Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, University Hospital Münster, Horstmarer Landweg 39, 48149, Münster, Germany

    Boris Schmitz & Stefan-Martin Brand

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  1. Katrin Guske
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Correspondence to Eva Brand.

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Guske, K., Schmitz, B., Schelleckes, M. et al. Tissue-specific differences in the regulation of KIBRA gene expression involve transcription factor TCF7L2 and a complex alternative promoter system. J Mol Med 92, 185–196 (2014). https://doi.org/10.1007/s00109-013-1089-y

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