title: Role of ALADIN in human adrenocortical cells for oxidative stress response and steroidogenesis.
abstract: Triple A syndrome is caused by mutations in AAAS encoding the protein ALADIN. We investigated the role of ALADIN in the human adrenocortical cell line NCI-H295R1 by either over-expression or down-regulation of ALADIN. Our findings indicate that AAAS knock-down induces a down-regulation of genes coding for type II microsomal cytochrome P450 hydroxylases CYP17A1 and CYP21A2 and their electron donor enzyme cytochrome P450 oxidoreductase, thereby decreasing biosynthesis of precursor metabolites required for glucocorticoid and androgen production. Furthermore we demonstrate that ALADIN deficiency leads to increased susceptibility to oxidative stress and alteration in redox homeostasis after paraquat treatment. Finally, we show significantly impaired nuclear import of DNA ligase 1, aprataxin and ferritin heavy chain 1 in ALADIN knock-down cells. We conclude that down-regulating ALADIN results in decreased oxidative stress response leading to alteration in steroidogenesis, highlighting our knock-down cell model as an important in-vitro tool for studying the adrenal phenotype in triple A syndrome.
authors: Klinik und Poliklinik für Kinder- und Jugendmedizin, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Germany.
authors: Ramona
authors: R
authors: Jühlen
authors: Centre for Endocrinology, Diabetes and Metabolism, School of Clinical & Experimental Medicine, University of Birmingham, United Kingdom.
authors: Jan
authors: J
authors: Idkowiak
authors: Centre for Endocrinology, Diabetes and Metabolism, School of Clinical & Experimental Medicine, University of Birmingham, United Kingdom.
authors: Angela E
authors: AE
authors: Taylor
authors: Klinik und Poliklinik für Kinder- und Jugendmedizin, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Germany.
authors: Barbara
authors: B
authors: Kind
authors: Centre for Endocrinology, Diabetes and Metabolism, School of Clinical & Experimental Medicine, University of Birmingham, United Kingdom.
authors: Wiebke
authors: W
authors: Arlt
authors: Klinik und Poliklinik für Kinder- und Jugendmedizin, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Germany.
authors: Angela
authors: A
authors: Huebner
authors: Klinik und Poliklinik für Kinder- und Jugendmedizin, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Germany.
authors: Katrin
authors: K
authors: Koehler
mesh_terms: D000302:Adrenal Cortex / Q000166:cytology / Q000378:metabolism*; D000728:Androgens / Q000096:biosynthesis*; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism; D020868:Gene Silencing; D005938:Glucocorticoids / Q000096:biosynthesis*; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000502:physiology*; D028861:Nuclear Pore Complex Proteins / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*
chemical_list: C416506:AAAS protein, human; D000728:Androgens; D005938:Glucocorticoids; D009419:Nerve Tissue Proteins; D028861:Nuclear Pore Complex Proteins; D006861:Hydrogen Peroxide; D005978:Glutathione; D019803:Glutathione Disulfide