Progesterone Receptor Transactivation of the Secretory Leukocyte Protease Inhibitor Gene in Ishikawa Endometrial Epithelial Cells Involves Recruitment of Krüppel-Like Factor 9/Basic Transcription Element Binding Protein-1

Abstract

Progesterone receptor (PR), a ligand-inducible transcription factor, mediates the physiological actions of progesterone (P) through two distinct isoforms, PR-A and PR-B, and numerous nuclear coregulators. We previously demonstrated that basic transcription element binding protein-1 (BTEB1), a transcription factor of the Krüppel-like family, is a functional PR-interacting protein, based on the subfertility phenotype and reduced P sensitivity of uterine PR target genes, on BTEB1 null mutation. Here we examined the role of BTEB1 in PR-mediated signaling in endometrial epithelial cells using Ishikawa human endocarcinoma cells and the P-responsive secretory leukocyte protease inhibitor (SLPI) gene. Treatment of Ishikawa cells with P for 24 h increased SLPI and BTEB1 transcript levels without similar effects on PR expression. P induction was abolished by the PR antagonist RU486, whereas knockdown of BTEB1 with short interfering RNA reduced P-responsive BTEB1 but not SLPI expression to basal levels. Forced expression of BTEB1, either by stable or transient transfections of BTEB1 expression constructs in endometrial carcinoma cells, enhanced SLPI promoter activity. Chromatin immunoprecipitation with anti-BTEB1 antibody demonstrated BTEB1 recruitment to the proximal GC-rich containing SLPI promoter region (-97 to -86) in human endometrial carcinoma (Hec1A) cells overexpressing BTEB1. In Ishikawa cells, recruitment of BTEB1 to the proximal, GC-rich region and the distal, progesterone-responsive element-like containing region (-635 to -514) was P dependent and was accompanied by corecruitment of PR and the PR coactivator cAMP-response element binding protein-binding protein. PR-B, rather than PR-A isoform, preferentially associated with BTEB1 in the GC-rich region, whereas both PR isoforms were recruited to the progesterone-responsive element-like site along with BTEB1. Our findings define a novel pathway for BTEB1/PR cross-talk to facilitate P-dependent gene transcription in endometrial epithelial cells.

The Glucocorticoid Receptor and KLF15 Regulate Gene Expression Dynamics and Integrate Signals through Feed-Forward Circuitry

“…Relatively little is known about how KLF family members achieve transcriptional specificity, as the information content provided by their preferred DNA binding sequences, the CACCC box and variants (49,50), is relatively limited. Our work indicates that specificity for KLF15 is conferred in part through composite elements containing both CACCC boxes and GBRs (51), which adds to a growing number of examples of combinatorial gene regulation by nuclear receptors and the KLF family (52)(53)(54)(55). Nuclear receptor signaling may thus impart specificity to the KLF family through a bipartite paradigm in which individual nuclear receptors both induce specific KLF family members and coregulate their transcriptional activity.…”

Structure–function relationship of estrogen receptor α and β: Impact on human health

“…The phylogenetic tree was performed by AliBee (available from: http://www.genebee.msu.su/index.html). GenBank accession codes: ERa (NP_000116) (Luisi et al, 2006), ERb (NP_001428) (Beleza-Meireles et al, 2006), ERRa (NP_004442) (Laflamme et al, 2005), ERRb (NP_004443) (Zhou et al, 2006), ERRc (NP_001429) (Liu et al, 2005), GR (NP_001018087) (Goleva et al, 2006), MR (NP_000892) , AR (NP_000035) (Alimirah et al, 2006), and PR (NP_000917) (Velarde et al, 2006). For details, see text.…”

Delayed Parturition and Altered Myometrial Progesterone Receptor Isoform A Expression in Mice Null for Krüppel-Like Factor 91

“…KLF9 enhances PGR-mediated transactivation in endometrial epithelial cells in vitro, in part by selective interactions with PGR-A and PGR-B isoforms under distinct physiological contexts [21,22,25]. Targeted deletion of Klf 9 resulted in subfertility due to reduced embryo implantation, decreased uterine stromal PGR expression, and attenuated uterine sensitivity to P [23,24].…”