Reversal of glucocorticoids-dependent proopiomelanocortin gene inhibition by leukemia inhibitory factor.

Abstract:

:We previously have described molecular mechanisms converging at the Nur response element-signal transducer and activator of transcription (STAT) composite site responsible for synergistic activation of the proopiomelanocortin (POMC) gene promoter by leukemia inhibitory factor (LIF) and CRH. In this study, we asked how glucocorticoids (GC), the physiological negative regulators of POMC gene expression, modulate this synergism. In the corticotroph cell line AtT-20, the response of the wild-type promoter to LIF+CRH was barely inhibited by GC, whereas a distal promoter subregion (-414/-293) encompassing the Nur response element-STAT site and devoid of the negative GC-responsive element located in the proximal domain, displayed a cooperative response to LIF+dexamethasone (DEX) and LIF+CRH+DEX treatments. LIF+CRH-stimulated ACTH secretion was also inefficiently inhibited by DEX in the same cell line. This study was focused thereafter on LIF+DEX cooperativity, which may be responsible, on the wild-type promoter, for lack of negative regulation by DEX of the LIF+CRH synergy. The STAT1-3 low-affinity site, in the context of the (-414/-293) subregion of the POMC promoter, was found necessary and sufficient for transcriptional synergism between activated GC receptor (GR) and STAT1-3. Moreover the activities of reporters specific for STAT1-3 or GR were reciprocally enhanced by DEX or LIF. Single and sequential chromatin immunoprecipitations revealed 1) a STAT-dependent corecruitment of coactivators after LIF and LIF+DEX stimulation and 2) a more lasting recruitment of both STAT3 and GR in the same enhanceosome on the endogenous POMC promoter after LIF+DEX joint stimulation than after the single one. Such events may be responsible for a lack of repressive property of GR unmasked on the whole POMC promoter during LIF+CRH stimulation and may contribute to the tonicity of the hypothalamic-pituitary-adrenal axis during inflammatory-infectious diseases.

journal_name

Endocrinology

journal_title

Endocrinology

authors

Latchoumanin O,Mynard V,Devin-Leclerc J,Dugué MA,Bertagna X,Catelli MG

doi

10.1210/en.2006-0460

subject

Has Abstract

pub_date

2007-01-01 00:00:00

pages

422-32

issue

1

eissn

0013-7227

issn

1945-7170

pii

en.2006-0460

journal_volume

148

pub_type

杂志文章