Tumor necrosis factor α receptor- and fas-associated FLASH inhibit transcriptional activity of the glucocorticoid receptor by binding to and interfering with its interaction with p160 type nuclear receptor coactivators

Tomoshige Kino, George P. Chrousos

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Tumor necrosis factor α (TNFα) and its downstream transcription factor nuclear factor κB (NF-κB) suppress glucocorticoid action, contributing to tissue resistance to glucocorticoids in several pathologic inflammatory states. p160 nuclear receptor coactivators on the other hand, contribute to the transcriptional signal of the glucocorticoid receptor (GR) through interaction with it via LXXLL motifs in their nuclear receptor-binding (NRB) domain. To discover TNFα-induced factors that regulate GR activity at the coactivator level, we performed yeast two-hybrid screening using the NRB domain of the glucocorticoid receptor-interacting protein 1 (GRIP1) as bait. We found that FLICE-associated huge protein (FLASH), which transduces TNFα and Fas ligand signals, bound the NRB domain of GRIP1 at a region between the second and third LXXLL motifs. FLASH suppressed both GR transactivation and GRIP1 enhancement of the glucocorticoid signal and inhibited the physical interaction between GR and the GRIP1 NRB domain. Transfected green fluorescent protein-fused FLASH was located in both the cytoplasm and nucleus, while endogenous FLASH shifted its subcellular localization from the cytoplasm into the nucleus in response to TNFα. FLASH antisense and super-repressor IκBα inhibited the action of TNFα independently of each other and additively. These findings indicate that FLASH participates in TNFα-induced blockade of GR transactivation at the nuclear receptor coactivator level, upstream and independently of NF-κB.

Original languageEnglish
Pages (from-to)3023-3029
Number of pages7
JournalJournal of Biological Chemistry
Volume278
Issue number5
DOIs
Publication statusPublished - 31 Jan 2003
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this