4.5 Article

Involvement of GR and p300 in the Induction of H6PD by Cortisol in Human Amnion Fibroblasts

Journal

ENDOCRINOLOGY
Volume 153, Issue 12, Pages 5993-6002

Publisher

ENDOCRINE SOC
DOI: 10.1210/en.2012-1531

Keywords

-

Funding

  1. National Key Basic Research Program of China [2011CB944403]
  2. Natural Science Foundation of China [30911120485]
  3. National Institutes of Health [R01 HD 31514]

Ask authors/readers for more resources

Human fetal membranes express 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1), which reduces biologically inert cortisone to active cortisol and may provide an extraadrenal source of cortisol mediating fetal development and parturition. The reductase activity of 11 beta-HSD1 depends on the availability of the cofactor reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) derived from the enzymatic activity of hexose-6-phosphodehydrogenase (H6PD). Based on the feed-forward induction of 11 beta-HSD1 by glucocorticoids in human fetal membranes, we hypothesize that glucocorticoids simultaneously induce H6PD in the fetal membranes. We found a parallel distribution of H6PD and 11 beta-HSD1 in the amnion, chorion, and decidua. In cultured human amnion fibroblasts, small interfering RNA-mediated knockdown of H6PD expression significantly attenuated the conversion of cortisone to cortisol. Cortisol (0.01-1 mu M) induced H6PD expression in a concentration-dependent manner, which was attenuated by glucocorticoid receptor (GR) antagonist RU486. Cortisol induced the expression of p300, a histone acetyltransferase, whereas C646, an inhibitor of p300, attenuated the induction of H6PD by cortisol. Coimmunoprecipitation revealed GR and p300 in the same nuclear protein complex upon cortisol stimulation. Chromatin immunoprecipitation showed that cortisol increased the binding of p300 and GR to H6PD promoter and the acetylation of histone 3 lysine 9 on the promoters. In conclusion, the induction of H6PD by cortisol requires the participation of GR and p300 as well as the acetylation of H3K9 by p300. This may be a prerequisite for the parallel induction of reductase activity of 11 beta-HSD1 in human amnion fibroblasts in a feed-forward loop that may influence fetal development and the onset of parturition. (Endocrinology 153: 5993-6002, 2012)

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.5
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available