title: Retinoic acid receptor beta and angiopoietin-like protein 1 are involved in the regulation of human androgen biosynthesis.
abstract: Androgens are essential for sexual development and reproduction. However, androgen regulation in health and disease is poorly understood. We showed that human adrenocortical H295R cells grown under starvation conditions acquire a hyperandrogenic steroid profile with changes in steroid metabolizing enzymes HSD3B2 and CYP17A1 essential for androgen production. Here we studied the regulatory mechanisms underlying androgen production in starved H295R cells. Microarray expression profiling of normal versus starved H295R cells revealed fourteen differentially expressed genes; HSD3B2, HSD3B1, CYP21A2, RARB, ASS1, CFI, ASCL1 and ENC1 play a role in steroid and energy metabolism and ANGPTL1, PLK2, DUSP6, DUSP10 and FREM2 are involved in signal transduction. We discovered two new gene networks around RARB and ANGPTL1, and show how they regulate androgen biosynthesis. Transcription factor RARB stimulated the promoters of genes involved in androgen production (StAR, CYP17A1 and HSD3B2) and enhanced androstenedione production. For HSD3B2 regulation RARB worked in cooperation with Nur77. Secretory protein ANGPTL1 modulated CYP17A1 and DUSP6 expression by inducing ERK1/2 phosphorylation. By contrast, our studies revealed no evidence for hormones or cell cycle involvement in regulating androgen biosynthesis. In summary, these studies establish a firm role for RARB and ANGPTL1 in the regulation of androgen production in H295R cells.
authors.affiliation: Pediatric Endocrinology and Diabetology, Department of Pediatrics, University Children's Hospital, Inselspital.|The Department of Clinical Research, University of Bern, 3010 Bern, Switzerland.
authors.forename: Sameer S
authors.initials: SS
authors.lastname: Udhane
authors.affiliation: Pediatric Endocrinology and Diabetology, Department of Pediatrics, University Children's Hospital, Inselspital.|The Department of Clinical Research, University of Bern, 3010 Bern, Switzerland.
authors.forename: Amit V
authors.initials: AV
authors.lastname: Pandey
authors.affiliation: Pediatric Endocrinology and Diabetology, Department of Pediatrics, University Children's Hospital, Inselspital.|The Department of Clinical Research, University of Bern, 3010 Bern, Switzerland.
authors.forename: Gaby
authors.initials: G
authors.lastname: Hofer
authors.affiliation: Pediatric Endocrinology and Diabetology, Department of Pediatrics, University Children's Hospital, Inselspital.|The Department of Clinical Research, University of Bern, 3010 Bern, Switzerland.
authors.forename: Primus E
authors.initials: PE
authors.lastname: Mullis
authors.affiliation: Pediatric Endocrinology and Diabetology, Department of Pediatrics, University Children's Hospital, Inselspital.|The Department of Clinical Research, University of Bern, 3010 Bern, Switzerland.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Flück
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism; D000728:Androgens / Q000096:biosynthesis*; D000091304:Angiopoietin-Like Protein 1; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000378:metabolism*; D002453:Cell Cycle; D002460:Cell Line; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism; D011375:Progesterone Reductase / Q000378:metabolism; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics; D013256:Steroids / Q000096:biosynthesis
chemical_list: C117578:ANGPTL1 protein, human; D000728:Androgens; D000091304:Angiopoietin-Like Protein 1; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018168:Receptors, Retinoic Acid; D013256:Steroids; C082925:retinoic acid receptor beta; C533068:3 beta-hydroxysteroid dehydrogenase type II; D011375:Progesterone Reductase; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3