title: Alternate surfaces of transcriptional coregulator GRIP1 function in different glucocorticoid receptor activation and repression contexts.
abstract: Members of the mammalian p160 family, such as GRIP1, are known as glucocorticoid receptor (GR) coactivators; at certain glucocorticoid response elements (GREs), however, GRIP1 acts as a GR corepressor. We characterized functional interactions of GR and GRIP1 in a repression complex where GR tethers to DNA-bound activator protein-1 (AP-1), as at the human collagenase-3 gene, and tested whether the identified interactions were similar or different at other response elements. At the AP-1 tethering GRE, we mapped the GRIP1 corepressor activity to a domain distinct from the two known GRIP1 activation domains; it exhibited intrinsic GR-independent repression potential when recruited to DNA via Gal4 DNA-binding domain. Interestingly, neither the domain nor the activity was detected in the other two p160 family members, SRC1 and RAC3. The same GRIP1 corepression domain was required for GR-mediated repression at the nuclear factor-kappaB (NF-kappaB) tethering GRE of the human IL-8 gene. In contrast, at the osteocalcin gene GRE, where GR represses transcription by binding to a DNA site overlapping the TATA box, both GRIP1 and SRC1 corepressed, and the GRIP1-specific repression domain was dispensable. Thus, in a single cell type, GR and GRIP1 conferred one mode of activation and two modes of repression by selectively engaging distinct surfaces of GRIP1 in a response element-specific manner.
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, 513 Parnassus Avenue, HSW1201, San Francisco, CA 94143-0450, USA.
authors.forename: Inez
authors.initials: I
authors.lastname: Rogatsky
authors.forename: Hans F
authors.initials: HF
authors.lastname: Luecke
authors.forename: Dale C
authors.initials: DC
authors.lastname: Leitman
authors.forename: Keith R
authors.initials: KR
authors.lastname: Yamamoto
mesh_terms: D002352:Carrier Proteins / Q000502:physiology; D004268:DNA-Binding Proteins; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000502:physiology; D051958:Nuclear Receptor Coactivator 2; D029543:Nucleocytoplasmic Transport Proteins; D015675:Osteocalcin / Q000235:genetics; D016601:RNA-Binding Proteins; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D020218:Response Elements; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C491719:MYBBP1A protein, human; C498001:NCOA2 protein, human; D016328:NF-kappa B; D009687:Nuclear Proteins; D051958:Nuclear Receptor Coactivator 2; D029543:Nucleocytoplasmic Transport Proteins; D016601:RNA-Binding Proteins; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D014157:Transcription Factors; D015675:Osteocalcin