PA1 protein, a new competitive decelerator acting at more than one step to impede glucocorticoid receptor-mediated transactivation. J Biol Chem 2013 Jan 04;288(1):42-58
Date
11/20/2012Pubmed ID
23161582Pubmed Central ID
PMC3537039DOI
10.1074/jbc.M112.427740Scopus ID
2-s2.0-84872069513 (requires institutional sign-in at Scopus site) 19 CitationsAbstract
Numerous cofactors modulate the gene regulatory activity of glucocorticoid receptors (GRs) by affecting one or more of the following three major transcriptional properties: the maximal activity of agonists (A(max)), the potency of agonists (EC(50)), and the partial agonist activity of antisteroids (PAA). Here, we report that the recently described nuclear protein, Pax2 transactivation domain interaction protein (PTIP)-associated protein 1 (PA1), is a new inhibitor of GR transactivation. PA1 suppresses A(max), increases the EC(50), and reduces the PAA of an exogenous reporter gene in a manner that is independent of associated PTIP. PA1 is fully active with, and strongly binds to, the C-terminal half of GR. PA1 reverses the effects of the coactivator TIF2 on GR-mediated gene induction but is unable to augment the actions of the corepressor SMRT. Analysis of competition assays between PA1 and TIF2 with an exogenous reporter indicates that the kinetic definition of PA1 action is a competitive decelerator at two sites upstream from where TIF2 acts. With the endogenous genes IGFBP1 and IP6K3, PA1 also represses GR induction, increases the EC(50), and decreases the PAA. ChIP and re-ChIP experiments indicate that PA1 accomplishes this inhibition of the two genes via different mechanisms as follows: PA1 appears to increase GR dissociation from and reduce GR transactivation at the IGFBP1 promoter regions but blocks GR binding to the IP6K3 promoter. We conclude that PA1 is a new competitive decelerator of GR transactivation and can act at more than one molecularly defined step in a manner that depends upon the specific gene.
Author List
Zhang Z, Sun Y, Cho YW, Chow CC, Simons SS JrAuthor
Yunguang Sun MD, PhD Assistant Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Binding SitesBinding, Competitive
Carrier Proteins
Cell Cycle Proteins
Cell Line
Cell Line, Tumor
DNA-Binding Proteins
Genes, Reporter
Glucocorticoids
Humans
Kinetics
Nuclear Proteins
Protein Binding
Protein Structure, Tertiary
RNA, Small Interfering
Receptors, Glucocorticoid
Transcriptional Activation
Two-Hybrid System Techniques
