Regulation of mineralocorticoid receptor activation by circadian protein TIMELESS

in Journal of Molecular Endocrinology
Authors:
Colin D ClyneCentre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Australia

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Kevin P KusnadiCardiovascular Endocrinology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia

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Alexander CowcherCentre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Australia

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James MorganCentre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Australia

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Jun YangCentre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Australia

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Peter J FullerCentre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Australia

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Morag J YoungCardiovascular Endocrinology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
University of Melbourne and Baker HDI Department of Cardiometabolic Health and Disease, Melbourne, Australia

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https://orcid.org/0000-0003-0450-5375
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Correspondence should be addressed to M J Young: morag.young@baker.edu.au

*(C D Clyne and K P Kusnadi contributed equally to this work)

DOI:
https://doi.org/10.1530/JME-21-0279
Volume/Issue:
Volume 70: Issue 1
Article Type:
Research Article
Article ID:
e210279
Online Publication Date:
07 Dec 2022
Copyright:
© Society for Endocrinology 2022
Restricted access

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The mineralocorticoid receptor (MR) is a ligand-activated transcription factor that regulates cardiorenal physiology and disease. Ligand-dependent MR transactivation involves a conformational change in the MR and recruitment of coregulatory proteins to form a unique DNA-binding complex at the hormone response element in target gene promoters. Differences in the recruitment of coregulatory proteins can promote tissue-, ligand- or gene-specific transcriptional outputs. The goal of this study was to evaluate the circadian protein TIMELESS as a selective regulator of MR transactivation. TIMELESS has an established role in cell cycle regulation and DNA repair. TIMELESS may not be central to mammalian clock function and does not bind DNA; however, RNA and protein levels oscillate over 24 h. Co-expression of TIMELESS down-regulated MR transactivation of an MR-responsive reporter in HEK293 cells, yet enhanced transactivation mediated by other steroid receptors. TIMELESS markedly inhibited MR transactivation of synthetic and native gene promoters and expression of MR target genes in H9c2 cardiac myoblasts. Immunofluorescence showed aldosterone induces colocalisation of TIMELESS and MR, although a direct interaction was not confirmed by coimmunoprecipitation. Potential regulation of circadian clock targets cryptochrome 1 and 2 by TIMELESS was not detected. However, our data suggest that these effects may involve TIMELESS coactivation of oestrogen receptor alpha (ERα). Taken together, these data suggest that TIMELESS may contribute to MR transcriptional outputs via enhancing ERα inhibitory actions on MR transactivation. Given the variable expression of TIMELESS in different cell types, these data offer new opportunities for the development of MR modulators with selective actions.

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Print ISSN:
0952-5041
Online ISSN:
1479-6813
Copyright:
© Society for Endocrinology 2022
Article ID:
e210279
Article Type:
Research Article
Received Date:
01 Sep 2022
Accepted Date:
13 Sep 2022
Print Publication Date:
01 Jan 2023
Online Publication Date:
07 Dec 2022
Keywords:
mineralocorticoid receptor; aldosterone; coregulator; circadian; TIMELESS; cortisol

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