Author : Jonathan M. Shipley
Publisher :
ISBN 13 :
Total Pages : 428 pages
Book Rating : 4.:/5 (298 download)
Book Synopsis Cross-talk Between Hormone-regulated Transcription Factors, STAT5b and ER, and Xenochemical Receptors, PPAR and AhR by : Jonathan M. Shipley
Download or read book Cross-talk Between Hormone-regulated Transcription Factors, STAT5b and ER, and Xenochemical Receptors, PPAR and AhR written by Jonathan M. Shipley and published by . This book was released on 2005 with total page 428 pages. Available in PDF, EPUB and Kindle. Book excerpt: Abstract: Nuclear receptors are ligand-inducible transcription factors that bind to DNA-response elements of target genes as monomers, homodimers, or as heterodimers with the retinoid X receptor. Two members of the nuclear receptor superfamily are peroxisome proliferator activated receptors (PPAR) and the estrogen receptor (ER). JAK-STAT signaling is activated by multiple cytokines and hormones, including growth hormone (GH), and leads to the translocation of dimerized STAT proteins to the nucleus where they activate transcription of target genes. Previous studies have demonstrated that STAT5b can inhibit PPAR-regulated transcription. Herein this inhibitory cross-talk is shown to be mutual, and that GH-induced, STAT5b-regulated, luciferase reporter gene transcription is inhibited up to 80% by ligand-activated PPAR. Mechanistic studies characterize aspects of PPAR/STAT5b cross-talk, including the effect of PPAR on STAT5b protein levels and DNA-binding activity, as well as the role of specific PPAR protein domains. A PPAR-activated Renilla luciferase reporter plasmid was constructed and used in combination with a STAT5b firefly luciferase reporter to show that in cells co-stimulated with GH and a PPAR agonist, STAT5b inhibition of PPAR-regulated transcription occurs simultaneous with PPAR inhibition of STAT5b-regulated transcription. Another example of cross-talk involving a nuclear receptor is aryl hydrocarbon receptor (AhR) inhibition of ER-regulated transcription. Recent studies have demonstrated a pro-estrogenic action of the AhR that proceeds via the formation of an (AhR-Arnt)-ER complex, which binds to estrogen response elements (EREs) and stimulates transcription of ER target genes. Activation by the AhR ligand, 3-methylcholanthrene (3MC), of an ER-regulated luciferase reporter and ER target genes in the breast cancer cell line MCF-7 is demonstrated. ER reporter activity is additionally activated by 3MC in the AhR-positive mouse hepatoma 5L cell line and its AhR-negative variant BP8. The ability of 3MC to activate ER-regulated transcription in the absence of AhR suggests that this AhR ligand may activate ER directly, instead of, or in addition to, the AhR-dependent mechanism proposed. Together, these studies elucidate mechanisms through which the xenochemical receptors PPAR and AhR may respectively exert crosstalk with hormone-activated signaling pathways involving STAT5b and ER.
