Factor recruitment and TIF2/GRIP1 corepressor activity at a collagenase-3 response element that mediates regulation by phorbol esters and hormones. Academic Article uri icon

Overview

abstract

  • To investigate determinants of specific transcriptional regulation, we measured factor occupancy and function at a response element, col3A, associated with the collagenase-3 gene in human U2OS osteosarcoma cells; col3A confers activation by phorbol esters, and repression by glucocorticoid and thyroid hormones. The subunit composition and activity of AP-1, which binds col3A, paralleled the intracellular level of cFos, which is modulated by phorbol esters and glucocorticoids. In contrast, a similar AP-1 site at the collagenase-1 gene, not inducible in U2OS cells, was not bound by AP-1. The glucocorticoid receptor (GR) associated with col3A through protein-protein interactions with AP-1, regardless of AP-1 subunit composition, and repressed transcription. TIF2/GRIP1, reportedly a coactivator for GR and the thyroid hormone receptor (TR), was recruited to col3A and potentiated GR-mediated repression in the presence of a GR agonist but not antagonist. GRIP1 mutants deficient in GR binding and coactivator functions were also defective for corepression, and a GRIP1 fragment containing the GR-interacting region functioned as a dominant-negative for repression. In contrast, repression by TR was unaffected by GRIP1. Thus, the composition of regulatory complexes, and the biological activities of the bound factors, are dynamic and dependent on cell and response element contexts. Cofactors such as GRIP1 probably contain distinct surfaces for activation and repression that function in a context-dependent manner.

publication date

  • November 1, 2001

Research

keywords

  • Collagenases
  • Gene Expression Regulation, Neoplastic
  • Osteosarcoma
  • Response Elements
  • Transcription Factors

Identity

PubMed Central ID

  • PMC125702

Scopus Document Identifier

  • 0035502975

Digital Object Identifier (DOI)

  • 10.1093/emboj/20.21.6071

PubMed ID

  • 11689447

Additional Document Info

volume

  • 20

issue

  • 21