Alternate surfaces of transcriptional coregulator GRIP1 function in different glucocorticoid receptor activation and repression contexts

• DOI: 10.1073/pnas.262671599
• Publication Date: 2002-12-23T18:14:48Z
• Authors: Inez Rogatsky; Hans F. Luecke; Dale C. Leitman; Keith R. Yamamoto
• Keywords: Nucleocytoplasmic Transport Proteins; 0303 health sciences; Osteocalcin; NF-kappa B; Nuclear Proteins; RNA-Binding Proteins; Response Elements; 3. Good health; DNA-Binding Proteins; Repressor Proteins; Nuclear Receptor Coactivator 2; 03 medical and health sciences; Receptors, Glucocorticoid; Tumor Cells, Cultured; Humans; Carrier Proteins; Transcription Factors

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-κB (NF-κB) 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.