Regulation of glucocorticoid receptor activity by a stress responsive transcriptional cofactor

Laura Davies, Elissavet Paraskevopoulou, Malihah Sadeq, Christiana Symeou, Constantia Pantelidou, Constantinos Demonacos, Marija Krstic-Demonacos

    Research output: Contribution to journalArticlepeer-review

    Abstract

    The activity of the glucocorticoid receptor (GR) is modulated by posttranslational modifications, protein stability, and cofactor recruitment. In this report, we investigated the role of the stressresponsive activator of p300/tetratricopeptide repeat domain 5 (TTC5), in the regulation of the GR. TTC5 is a member of the TTC family of proteins and has previously been shown to participate in the cellular response to DNA damage and heat shock. Here, we demonstrate that TTC5 is an important cofactor for the nuclear hormone receptors GR and estrogen receptor. GR and TTC5 interact through multiple tetratricopeptide repeat and LXXLL motifs. TTC5 stabilizes GR and increases its half-life, through a proteasome-dependent process and by inhibiting the actions of the ubiquitin ligase murine double minute 2. Cellular stress, including DNA damage, proteasome inhibition, and heat shock, modulates the interaction pattern of GR/TTC5, thereby altering GR stability and transcriptional activity. Furthermore, GR transcriptional activity is regulated by TTC5 in both a positive and negative fashion under DNA damage conditions in a target gene-specific way. In this report we provide evidence supporting the notion that TTC5 is a novel cofactor regulating GR function in a stress-dependent manner. (Molecular Endocrinology 25: 58-71, 2011). Copyright © 2011 by The Endocrine Society.
    Original languageEnglish
    Pages (from-to)58-71
    Number of pages13
    JournalMolecular Endocrinology
    Volume25
    Issue number1
    DOIs
    Publication statusPublished - Jan 2011

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