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
Copyright policy )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
Tumor necrosis factor alpha (TNF alpha) and its downstream transcription factor nuclear factor kappa B (NF-kappa B) 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 TNF alpha-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 TNF alpha 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 TNF alpha. FLASH antisense and super-repressor I kappa B alpha inhibited the action of TNF alpha independently of each other and additively. These findings indicate that FLASH participates in TNF alpha-induced blockade of GR transactivation at the nuclear receptor coactivator level, upstream and independently of NF-kappa B.
- National Institute of Health Pakistan
- National Institutes of Health United States
Cell Nucleus, Nucleocytoplasmic Transport Proteins, Binding Sites, Calcium-Binding Proteins, Nuclear Proteins, RNA-Binding Proteins, Receptors, Cytoplasmic and Nuclear, Saccharomyces cerevisiae, Receptors, Tumor Necrosis Factor, Recombinant Proteins, Cell Line, DNA-Binding Proteins, Protein Transport, Receptors, Glucocorticoid, Humans, Amino Acid Sequence, Cloning, Molecular, Apoptosis Regulatory Proteins, Carrier Proteins, Transcription Factors
Cell Nucleus, Nucleocytoplasmic Transport Proteins, Binding Sites, Calcium-Binding Proteins, Nuclear Proteins, RNA-Binding Proteins, Receptors, Cytoplasmic and Nuclear, Saccharomyces cerevisiae, Receptors, Tumor Necrosis Factor, Recombinant Proteins, Cell Line, DNA-Binding Proteins, Protein Transport, Receptors, Glucocorticoid, Humans, Amino Acid Sequence, Cloning, Molecular, Apoptosis Regulatory Proteins, Carrier Proteins, Transcription Factors
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