Endocrine Abstracts

Glucocorticoid receptor (GR) is a ligand-dependent nuclear receptor which regulates the transcription of a wide spectrum of genes that are responsible for vital immunological, metabolic, developmental, and anti-inflammatory functions. GR transcriptional regulatory effects are modulated by co-regulators including the tetratricopeptide 5 (TTC5) which has been shown to stabilize GR and alter its action in response to cellular stress. TTC5 is a stress-responsive activator of p300 and its activities are controlled by the ataxia telangiectasia mutated (ATM) and Chk2 kinases. TTC5 is comprised of six TPRs in addition to four probable nuclear receptor (NR) LXXLL boxes. Here we provide evidence to suggest that in A549 lung cancer cells different LXXLL motifs in TTC5 are required to differentially inhibit GR mediated transcriptional function on the TAT-3 promoter in a hormone-dependent manner, whereas association of GR with TTC5 through the co-regulator’s TPR sequences increased GR mediated TAT-3 gene expression. Furthermore, TTC5 and GR sub cellular co-localization occurred in a mode dependent on the presence of hormone as well as the integrity of the LXXLL domains located in the TTC5 N terminus. We conclude that TTC5 plays a dual function in the control of GR mediated gene expression and its sub cellular location depending on the surface of TTC5 utilized to interact with the receptor.