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Association of the glucocorticoid receptor with STAT3, C/EBPbeta, and the hormone-responsive element within the rat haptoglobin gene promoter during the acute phase response.

Abstract：

:Upregulation of haptoglobin (Hp) expression in the rat during the acute phase (AP) response is the result of synergistic effects of IL-6-, IL-1beta-, and corticosterone-activated signaling pathways. IL-6 signaling terminates in cis-trans interactions of the Hp gene hormone-responsive element (HRE) with transcription factors STAT3 and C/EBPbeta. The aim of this study was to examine the unresolved molecular mechanism of glucocorticoid action. A 3-fold rise in serum corticosterone at 2 and 4 h of the AP response induced by turpentine administration preceded a 2.3-fold increase in the rate of Hp gene transcription at 12 h that was accompanied by a 4.8-fold increase in glucocorticoid receptor (GR), the appearance of an 86-kDa STAT3 isoform and 3.9-, 1.9-, and 1.7-fold increased amounts of 91-kDa STAT3, 35- and 42-kDa C/EBPbeta isoforms in the nucleus. These events resulted in 4.6- and 2.5-fold increased Hp levels in the liver and serum at 24 h. HRE affinity chromatography and immunoblot analysis revealed that maximal occupancy of the HRE with GR, STAT3, and C/EBPbeta at 12 h correlated with increased transcriptional activity of the Hp gene. Coimmunoprecipitation experiments showed that activated GR established de novo interaction with STAT3 isoforms while GR-C/EBPbeta interactions observed during basal transcription increased during the AP response. Computer analysis of the HRE disclosed two potential GR-binding sites: one overlapping STAT3, another adjacent to a C/EBPbeta-binding site. This finding and the experimental results suggest that activated GR through direct interactions with STAT3 and C/EBPbeta, participates in Hp gene upregulation as a transcriptional coactivator.

journal_name

IUBMB Life

journal_title

IUBMB life

authors

Arambasić J,Poznanović G,Ivanović-Matić S,Bogojević D,Mihailović M,Uskoković A,Grigorov I

doi

10.1002/iub.313

subject

Has Abstract

pub_date

2010-03-01 00:00:00

pages

227-36

issue

eissn

1521-6543

issn

1521-6551

journal_volume

pub_type

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Association of the glucocorticoid receptor with STAT3, C/EBPbeta, and the hormone-responsive element within the rat haptoglobin gene promoter during the acute phase response.