title: Regulation of glucocorticoid receptor activity by a stress responsive transcriptional cofactor.
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 stress-responsive 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.
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Oxford Road, Manchester, England, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Davies
authors.forename: Elissavet
authors.initials: E
authors.lastname: Paraskevopoulou
authors.forename: Malihah
authors.initials: M
authors.lastname: Sadeq
authors.forename: Christiana
authors.initials: C
authors.lastname: Symeou
authors.forename: Constantia
authors.initials: C
authors.lastname: Pantelidou
authors.forename: Constantinos
authors.initials: C
authors.lastname: Demonacos
authors.forename: Marija
authors.initials: M
authors.lastname: Krstic-Demonacos
mesh_terms: D000818:Animals; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D008954:Models, Biological; D011401:Promoter Regions, Genetic / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D025941:Protein Interaction Mapping; D055550:Protein Stability / Q000187:drug effects; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid; C557280:TTC5 protein, human; D014157:Transcription Factors; D003907:Dexamethasone; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex