A second pathway for modulating glucocorticoid receptor transactivation properties.
We recently reported that three factors (a cis-acting element and changing concentrations of receptor or coactivator TIF2) act at a common rate-limiting step to modulate the position of the dose-response curve and the partial agonist activity of glucocorticoid receptors (GRs). The ability of saturating levels of GR, and added inhibitors, to prevent the actions of the three modulators (cis-acting element, GR, and TIF2) but not the currently investigated C-terminal fragment of E1A-13S (E1A-133C) indicates that E1A-133C alters GR properties via a second pathway that is downstream of the common step for the original three modulators. hSur2 binds to E1A-133C. We find that hSur2 modulates GR transactivation properties, thus suggesting that the effects of E1A-133C are due to the recruitment of hSur2. hSur2 also modifies GR activities in the presence of saturating GR concentrations, which is consistent with hSur2 acting downstream of the common step for the original three modulators. The H160Y mutation, which eliminates hSur2 binding to E1A, blocks most of the activity of E1A-133C. This suggests that the modulatory activity of E1A-133C is largely due to the binding of hSur2, which is a component of the Mediator complex. Collectively, these data support the existence of a new pathway for modulating GR transactivation processes, thereby increasing the number of cellular mechanisms that permit differential control of gene expression by endogenous levels of glucocorticoid hormones.
Chen
Shiyou
S
Steroid Hormones Section, NIDDK/LMCB, National Institutes of Health (NIH), Building 8, Room B2A-07, Bethesda, MD 20892, USA.
Simons
S Stoney
SS
D017500:Adenovirus E1A Proteins / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D056892:Mediator Complex; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D017354:Point Mutation; D011485:Protein Binding / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects
D017500:Adenovirus E1A Proteins; C492159:MED23 protein, human; D056892:Mediator Complex; D010446:Peptide Fragments; D011965:Receptors, Glucocorticoid; D015534:Trans-Activators; D014157:Transcription Factors; D003907:Dexamethasone