Show simple item record

dc.contributor.authorNorris, John D.
dc.contributor.authorFan, Daju
dc.contributor.authorStallcup, Michael R.
dc.contributor.authorMcDonnell, Donald P.
dc.date.accessioned2018-08-24T08:25:53Z
dc.date.available2018-08-24T08:25:53Z
dc.date.issued1998-03-20
dc.identifier.citationNorris, John D. Fan, Daju; Stallcup, Michael R.; McDonnell, Donald P. (1998). Enhancement of estrogen receptor transcriptional activity by the coactivator grip-1 highlights the role of activation function 2 in determining estrogen receptor pharmacology. Journal of Biological Chemistry 273 (12), 6679-6688
dc.identifier.issn0021-9258,1083-351X
dc.identifier.urihttp://hdl.handle.net/10379/9632
dc.description.abstractThe human estrogen receptor (ER) contains two major activation functions (AFs) responsible for its transcriptional activity. One of these, activation function 2 (AF-2), located within the hormone-binding domain (HBD), has been shown to mediate the ligand-dependent transcriptional activity of ER as well as other members of the nuclear receptor superfamily. Recently, proteins interacting with the HBD of several nuclear receptors have been cloned. One of these proteins, glucocorticoid receptor interacting protein (GRIP-1), has been shown to interact with ER and was originally hypothesized to mediate its transcriptional activity through AF-2. However, we find in this study that the transcriptional activity of ER, containing mutations in the AF-2 core sequence, can be enhanced by coexpression of the coactivator GRIP-I, suggesting that this protein may not rely solely on the AF-2 domain for interaction. We propose, therefore, that the HBD of ER either contains multiple binding sites that are necessary for association with GRIP-I or, alternatively, that this coactivator contacts the receptor in an undetermined region within the HBD. Importantly, these studies demonstrate also that mutations or deletion of AF-2 alter the ligand pharmacology of the receptor such that ER loses the ability to discriminate between agonists and antagonists. Interestingly, on these mutant receptors GRIP-I still functions as a coactivator independent of the nature of the bound ligand. It is likely, therefore, that the C-terminal AF-2 domain may function as a molecular switch allowing the wild-type receptor to discriminate between agonists and antagonists as well as providing a surface with which associated proteins can interact.
dc.publisherAmerican Society for Biochemistry & Molecular Biology (ASBMB)
dc.relation.ispartofJournal of Biological Chemistry
dc.subjectthyroid-hormone receptor
dc.subjectligand-binding domain
dc.subjecthuman progesterone-receptor
dc.subjectmixed agonist activity
dc.subjectnuclear receptors
dc.subjectresponsive element
dc.subjectretinoic acid
dc.subjecttransactivation domain
dc.subjectsteroid-receptors
dc.subjectpromoter-context
dc.titleEnhancement of estrogen receptor transcriptional activity by the coactivator grip-1 highlights the role of activation function 2 in determining estrogen receptor pharmacology
dc.typeArticle
dc.identifier.doi10.1074/jbc.273.12.6679
dc.local.publishedsourcehttp://www.jbc.org/content/273/12/6679.full.pdf
nui.item.downloads0


Files in this item

This item appears in the following Collection(s)

Show simple item record