title: Development of pheochromocytoma in ceramide synthase 2 null mice.
abstract: Pheochromocytoma (PCC) and paraganglioma are rare neuroendocrine tumors of the adrenal medulla and sympathetic and parasympathetic paraganglia, for which mutations in ∼15 disease-associated genes have been identified. We now document the role of an additional gene in mice, the ceramide synthase 2 (CerS2) gene. CerS2, one of six mammalian CerS, synthesizes ceramides with very-long (C22-C24) chains. The CerS2 null mouse has been well characterized and displays lesions in several organs including the liver, lung and the brain. We now demonstrate that changes in the sphingolipid acyl chain profile of the adrenal gland lead to the generation of adrenal medullary tumors. Histological analyses revealed that about half of the CerS2 null mice developed PCC by ∼13 months, and the rest showed signs of medullary hyperplasia. Norepinephrine and normetanephrine levels in the urine were elevated at 7 months of age consistent with the morphological abnormalities found at later ages. Accumulation of ceroid in the X-zone was observed as early as 2 months of age and as a consequence, older mice displayed elevated levels of lysosomal cathepsins, reduced proteasome activity and reduced activity of mitochondrial complex IV by 6 months of age. Together, these findings implicate an additional pathway that can lead to PCC formation, which involves alterations in the sphingolipid acyl chain length. Analysis of the role of sphingolipids in PCC may lead to further understanding of the mechanism by which PCC develops, and might implicate the sphingolipid pathway as a possible novel therapeutic target for this rare tumor.
authors.affiliation: Department of Biological ChemistryWeizmann Institute of Science, Rehovot 76100, IsraelDepartment of BiochemistrySchool of Medicine, Gachon University, Incheon 406-799, South KoreaDepartment of Veterinary ResourcesWeizmann Institute of Science, Rehovot 76100, IsraelMonique and Jacques Roboh Department of Genetic ResearchDepartment of Genetics and Metabolic Diseases, Hadassah, Hebrew University Medical Center, Jerusalem, IsraelSchool of Biology and Petit Institute for Bioengineering and BioscienceGeorgia Institute of Technology, Atlanta, Georgia 30332-0230, USA Department of Biological ChemistryWeizmann Institute of Science, Rehovot 76100, IsraelDepartment of BiochemistrySchool of Medicine, Gachon University, Incheon 406-799, South KoreaDepartment of Veterinary ResourcesWeizmann Institute of Science, Rehovot 76100, IsraelMonique and Jacques Roboh Department of Genetic ResearchDepartment of Genetics and Metabolic Diseases, Hadassah, Hebrew University Medical Center, Jerusalem, IsraelSchool of Biology and Petit Institute for Bioengineering and BioscienceGeorgia Institute of Technology, Atlanta, Georgia 30332-0230, USA.
authors.forename: Woo-Jae
authors.initials: WJ
authors.lastname: Park
authors.affiliation: Department of Biological ChemistryWeizmann Institute of Science, Rehovot 76100, IsraelDepartment of BiochemistrySchool of Medicine, Gachon University, Incheon 406-799, South KoreaDepartment of Veterinary ResourcesWeizmann Institute of Science, Rehovot 76100, IsraelMonique and Jacques Roboh Department of Genetic ResearchDepartment of Genetics and Metabolic Diseases, Hadassah, Hebrew University Medical Center, Jerusalem, IsraelSchool of Biology and Petit Institute for Bioengineering and BioscienceGeorgia Institute of Technology, Atlanta, Georgia 30332-0230, USA.
authors.forename: Ori
authors.initials: O
authors.lastname: Brenner
authors.affiliation: Department of Biological ChemistryWeizmann Institute of Science, Rehovot 76100, IsraelDepartment of BiochemistrySchool of Medicine, Gachon University, Incheon 406-799, South KoreaDepartment of Veterinary ResourcesWeizmann Institute of Science, Rehovot 76100, IsraelMonique and Jacques Roboh Department of Genetic ResearchDepartment of Genetics and Metabolic Diseases, Hadassah, Hebrew University Medical Center, Jerusalem, IsraelSchool of Biology and Petit Institute for Bioengineering and BioscienceGeorgia Institute of Technology, Atlanta, Georgia 30332-0230, USA Department of Biological ChemistryWeizmann Institute of Science, Rehovot 76100, IsraelDepartment of BiochemistrySchool of Medicine, Gachon University, Incheon 406-799, South KoreaDepartment of Veterinary ResourcesWeizmann Institute of Science, Rehovot 76100, IsraelMonique and Jacques Roboh Department of Genetic ResearchDepartment of Genetics and Metabolic Diseases, Hadassah, Hebrew University Medical Center, Jerusalem, IsraelSchool of Biology and Petit Institute for Bioengineering and BioscienceGeorgia Institute of Technology, Atlanta, Georgia 30332-0230, USA.
authors.forename: Aviram
authors.initials: A
authors.lastname: Kogot-Levin
authors.affiliation: Department of Biological ChemistryWeizmann Institute of Science, Rehovot 76100, IsraelDepartment of BiochemistrySchool of Medicine, Gachon University, Incheon 406-799, South KoreaDepartment of Veterinary ResourcesWeizmann Institute of Science, Rehovot 76100, IsraelMonique and Jacques Roboh Department of Genetic ResearchDepartment of Genetics and Metabolic Diseases, Hadassah, Hebrew University Medical Center, Jerusalem, IsraelSchool of Biology and Petit Institute for Bioengineering and BioscienceGeorgia Institute of Technology, Atlanta, Georgia 30332-0230, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Saada
authors.affiliation: Department of Biological ChemistryWeizmann Institute of Science, Rehovot 76100, IsraelDepartment of BiochemistrySchool of Medicine, Gachon University, Incheon 406-799, South KoreaDepartment of Veterinary ResourcesWeizmann Institute of Science, Rehovot 76100, IsraelMonique and Jacques Roboh Department of Genetic ResearchDepartment of Genetics and Metabolic Diseases, Hadassah, Hebrew University Medical Center, Jerusalem, IsraelSchool of Biology and Petit Institute for Bioengineering and BioscienceGeorgia Institute of Technology, Atlanta, Georgia 30332-0230, USA.
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Merrill
authors.affiliation: Department of Biological ChemistryWeizmann Institute of Science, Rehovot 76100, IsraelDepartment of BiochemistrySchool of Medicine, Gachon University, Incheon 406-799, South KoreaDepartment of Veterinary ResourcesWeizmann Institute of Science, Rehovot 76100, IsraelMonique and Jacques Roboh Department of Genetic ResearchDepartment of Genetics and Metabolic Diseases, Hadassah, Hebrew University Medical Center, Jerusalem, IsraelSchool of Biology and Petit Institute for Bioengineering and BioscienceGeorgia Institute of Technology, Atlanta, Georgia 30332-0230, USA yael.pewzner-jung@weizmann.ac.il.
authors.forename: Yael
authors.initials: Y
authors.lastname: Pewzner-Jung
authors.affiliation: Department of Biological ChemistryWeizmann Institute of Science, Rehovot 76100, IsraelDepartment of BiochemistrySchool of Medicine, Gachon University, Incheon 406-799, South KoreaDepartment of Veterinary ResourcesWeizmann Institute of Science, Rehovot 76100, IsraelMonique and Jacques Roboh Department of Genetic ResearchDepartment of Genetics and Metabolic Diseases, Hadassah, Hebrew University Medical Center, Jerusalem, IsraelSchool of Biology and Petit Institute for Bioengineering and BioscienceGeorgia Institute of Technology, Atlanta, Georgia 30332-0230, USA.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000652:urine; D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D002395:Catecholamines / Q000652:urine; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism; D005260:Female; D008297:Male; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D010673:Pheochromocytoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000652:urine; D051049:Sphingosine N-Acyltransferase / Q000235:genetics*
chemical_list: D002395:Catecholamines; C580723:Cers2 protein, mouse; D051049:Sphingosine N-Acyltransferase; D002403:Cathepsins
keywords: acyl chain length; ceramide; ceroid; lipofuscin; oxidative stress; pheochromocytoma; sphingolipid