CCAAT/enhancer binding protein beta regulates aromatase expression via multiple and novel cis-regulatory sequences in uterine leiomyoma

The Journal of Clinical Endocrinology and Metabolism
Hiroshi IshikawaS E Bulun

Abstract

Control of aromatase expression in uterine leiomyoma has significant clinical implications because aromatase inhibitors reduce tumor growth and associated irregular uterine bleeding. The mechanisms that regulate aromatase expression in leiomyoma are unknown. We previously demonstrated that the cAMP-responsive proximal promoters I.3 and II regulate aromatase expression in vivo in uterine leiomyoma tissue. Here, we investigated the cellular and molecular mechanisms responsible for promoter I.3/II usage. In smooth muscle cells isolated from leiomyoma (LSMCs), dibutyryl cAMP significantly induced aromatase mRNA and enzyme activity. Reporter constructs of promoter I.3/II deletion and site-directed mutants with selective disruption of cis-regulatory elements in the -517/-16 bp region revealed that five out of seven elements, including three CCAAT/enhancer binding protein (C/EBP) binding sites and two cAMP response elements, were essential for cAMP-induced promoter activity. EMSAs demonstrated that nuclear extracts from LSMCs contain complexes assembled on four of the five cis-elements, with C/EBP binding sites, including a novel -245/-231 bp sequence, clearly associating with C/EBPbeta. Chromatin immunoprecipitation assays revealed t...Continue Reading

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Citations

Oct 4, 2013·The New England Journal of Medicine·Serdar E Bulun
Feb 26, 2009·The Journal of Clinical Endocrinology and Metabolism·Hiroshi IshikawaSerdar E Bulun
May 10, 2012·PloS One·Masanori OnoSerdar E Bulun
Jul 21, 2011·Journal of Osteoporosis·Daniela MerlottiRanuccio Nuti
Sep 11, 2014·Human Reproduction Update·Molly B MoravekSerdar E Bulun
Nov 23, 2016·Reproductive Sciences·Mostafa A BorahayAyman Al-Hendy
Mar 23, 2017·The Journal of Clinical Endocrinology and Metabolism·Molly B MoravekSerdar E Bulun
Aug 4, 2018·Irish Journal of Medical Science·Feras Abu SaadehNoreen Gleeson
Jun 25, 2015·Current Opinion in Obstetrics & Gynecology·Molly B Moravek, Serdar E Bulun
Dec 10, 2020·Journal of Clinical Medicine·Jacques Donnez

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