title: The mRNA-binding protein HuR is regulated in the menstrual cycle and repressed in ectopic endometrium.
abstract: Cytokines modulate turnover of the endometrium during the menstrual cycle and contribute to the pathogenesis of endometriosis. Gene expression for cytokines is often regulated by proteins that bind to adenosine- and uridine-rich elements (AREs) in their transcripts to stabilize or destabilize bound messenger RNAs (mRNAs). HuR/ELAVL1 is an RNA-binding protein that stabilizes ARE-containing mRNAs. We hypothesized that HuR might play a role in regulating cytokine expression during the menstrual cycle and in endometriosis and characterized the expression and regulation of HuR in eutopic and ectopic human endometrium. Tissue sections obtained from normal (n = 23) and ectopic (n = 16) endometrium were immunostained for HuR, and staining intensity was evaluated by HSCORE. Cultured stromal cells isolated from normal endometrium were treated with vehicle, estradiol (E2), progesterone (P), E2 + P, tumor necrosis factor-α (TNF-α), and interleukin 1β (IL-1β) for 24 hours, and HuR expression was determined by Western blot. HuR immunoreactivity was significantly lower in the early proliferative and late secretory phases (157.5 ± 11.08 and 190.0 ± 15.2, respectively), compared to the mid-late proliferative (270.0 ± 8.0) and early-mid secretory phases (256.6 ± 20.2; P < .01, analysis of variance [ANOVA]). Furthermore, HuR expression was significantly lower in ectopic endometrial cells compared to normal endometrium in mid-late proliferative and early-mid-secretory phases (P < .01). Estrogen, P, or cytokines did not alter HuR expression in cultured endometrial stromal cells. Increased HuR levels in the mid-menstrual phases are likely to contribute to reduced mid-cycle cytokine expression and enhanced cellular survival in eutopic endometrium. In ectopic endometrium, elevated cytokine levels associated with endometriosis likely reduce HuR expression.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, 06520, USA.
authors.forename: Fethiye Sinem
authors.initials: FS
authors.lastname: Karipcin
authors.forename: Tugba Altun
authors.initials: TA
authors.lastname: Ensari
authors.forename: Umit A
authors.initials: UA
authors.lastname: Kayisli
authors.forename: Elif
authors.initials: E
authors.lastname: Guzel
authors.forename: Caleb B
authors.initials: CB
authors.lastname: Kallen
authors.forename: Emre
authors.initials: E
authors.lastname: Seli
mesh_terms: D000954:Antigens, Surface / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D004715:Endometriosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004717:Endometrium / Q000166:cytology / Q000502:physiology*; D004967:Estrogens / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008597:Menstrual Cycle / Q000502:physiology*; D011374:Progesterone / Q000502:physiology; D020871:RNA Stability / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D004967:Estrogens; D053583:Interleukin-1beta; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; D011374:Progesterone