Endocrine Abstracts (2012) 28 OC4.8

The role of a novel co-regulator in modifying the transcriptonal activities of the glucocorticoid receptor

Malihah Sadeq, Costas Demonacos & Marija Krstic-Demonacos

Faculty of Life sciences, University of Manchester, Manchester, United Kingdom.

Glucocorticoid receptor (GR) is a hormone-dependent nuclear transcription factor that modulates the expression of genes involved in development, inflammation, and metabolism. In addition, as GR is a key factor in several steroid dependent cancers steroid hormones are extensively used in the treatment of cancers such as leukemia. The transcriptional activity of GR is cell type specific and its magnitude and target selectivity depend on multiple factors including posttranslational modifications and co-regulators. TTC5 (tetratricopeptide repeat domain (TPR) 5) is a stress responsive activator of p300 and co-regulator of several nuclear transcription factors including p53 and GR. Four LXXLL nuclear receptor interacting motifs have been identified in TTC5 in this study together with six tandem TPRs that have been reported previously. We hypothesised that these motifs individually confer specific features to the function of GR differentially affecting its transcriptional activity, protein stability, nuclear location and gene target specificity under diverse environmental conditions. Here we demonstrate that the LXXLL motifs (L278A, L16A, V145A, L289A) are probable co-repressor boxes. Our results suggested that in transfected cells, mutant LXXLL motifs increase GR activity on TAT-3 promoter. In addition, overexpression of mutant TTC5 up-regulates the mRNA levels of a subset of GR endogenous target genes and alters the GR protein levels. Accordingly, the four LXXLL motifs exerted repressive effect on GR in a promoter and a stress signal dependent manner. Taken together these results support the notion that different TTC5 motifs function either as the GR corepressors or coactivators possibly through changing the multiprotein complex composition depending on diverse stress signals.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.

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