title: Up-regulation of 11β-Hydroxysteroid Dehydrogenase Type 2 Expression by Hedgehog Ligand Contributes to the Conversion of Cortisol Into Cortisone.
abstract: The cortisol-inactivating enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) that catalyzes the intracellular inactivation of glucocorticoids plays a pivotal role in human pregnant maintenance and normal fetal development. Given the fact that the main components of Hedgehog (HH) signaling pathway are predominantly expressed in syncytial layer of human placental villi where 11β-HSD2 is robustly expressed, in the present study, we have investigated the potential roles and underlying mechanisms of HH signaling in 11β-HSD2 expression. Activation of HH signaling by a variety of approaches robustly induced 11β-HSD2 expression as well as the 11β-HSD2 activity, whereas suppression of HH signaling significantly attenuated 11β-HSD2 expression as well as the 11β-HSD2 activity in both human primary cytotrophoblasts and trophoblast-like BeWo cells. Moreover, among glioma-associated oncogene (GLI) family transcriptional factors in HH signaling, knockdown of GLI2 but not GLI1 and GLI3 significantly attenuated HH-induced 11β-HSD2 expression and activity, and overexpression of GLI2 activator alone was sufficient to induce 11β-HSD2 expression and activity. Finally, GLI2 not only directly bound to the promoter region of gene hsd11b2 to transactivate hsd11b2 but also formed a heterodimer with RNA polymerase II, an enzyme that catalyzes the transcription of DNA to synthesize mRNAs, resulting in up-regulation of hsd11b2 gene transcription. Taken together, the present study has uncovered a hitherto uncharacterized role of HH/GLI2 signaling in 11β-HSD2 regulation, implicating that HH signaling through GLI2 could be required for the human pregnant maintenance and fetal development.
authors.affiliation: Department of Obstetrics and Gynaecology (H.Z.), The First Affiliated Hospital, and Department of Endocrinology (C.Z., W.X., L.T.), The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, People's Republic of China; and Department of Pharmacology (X.F., X.W., C.T.), School of Medicine, Zhejiang University, Hangzhou 310058, People's Republic of China.
authors.forename: Haibin
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Obstetrics and Gynaecology (H.Z.), The First Affiliated Hospital, and Department of Endocrinology (C.Z., W.X., L.T.), The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, People's Republic of China; and Department of Pharmacology (X.F., X.W., C.T.), School of Medicine, Zhejiang University, Hangzhou 310058, People's Republic of China.
authors.forename: Chaochun
authors.initials: C
authors.lastname: Zou
authors.affiliation: Department of Obstetrics and Gynaecology (H.Z.), The First Affiliated Hospital, and Department of Endocrinology (C.Z., W.X., L.T.), The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, People's Republic of China; and Department of Pharmacology (X.F., X.W., C.T.), School of Medicine, Zhejiang University, Hangzhou 310058, People's Republic of China.
authors.forename: Xueying
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Obstetrics and Gynaecology (H.Z.), The First Affiliated Hospital, and Department of Endocrinology (C.Z., W.X., L.T.), The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, People's Republic of China; and Department of Pharmacology (X.F., X.W., C.T.), School of Medicine, Zhejiang University, Hangzhou 310058, People's Republic of China.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Xiong
authors.affiliation: Department of Obstetrics and Gynaecology (H.Z.), The First Affiliated Hospital, and Department of Endocrinology (C.Z., W.X., L.T.), The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, People's Republic of China; and Department of Pharmacology (X.F., X.W., C.T.), School of Medicine, Zhejiang University, Hangzhou 310058, People's Republic of China.
authors.forename: Lanfang
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Obstetrics and Gynaecology (H.Z.), The First Affiliated Hospital, and Department of Endocrinology (C.Z., W.X., L.T.), The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, People's Republic of China; and Department of Pharmacology (X.F., X.W., C.T.), School of Medicine, Zhejiang University, Hangzhou 310058, People's Republic of China.
authors.forename: Ximei
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Obstetrics and Gynaecology (H.Z.), The First Affiliated Hospital, and Department of Endocrinology (C.Z., W.X., L.T.), The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, People's Republic of China; and Department of Pharmacology (X.F., X.W., C.T.), School of Medicine, Zhejiang University, Hangzhou 310058, People's Republic of China.
authors.forename: Chao
authors.initials: C
authors.lastname: Tang
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D011247:Pregnancy; D012319:RNA Polymerase II / Q000378:metabolism; D000072086:Smoothened Receptor / Q000378:metabolism; D014327:Trophoblasts / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1 / Q000378:metabolism; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3
chemical_list: C400551:GLI1 protein, human; C082593:GLI2 protein, human; C065683:GLI3 protein, human; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000072086:Smoothened Receptor; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human; D012319:RNA Polymerase II; D006854:Hydrocortisone