title: Selenophosphate synthetase 1 is an essential protein with roles in regulation of redox homoeostasis in mammals.
abstract: Selenophosphate synthetase (SPS) was initially detected in bacteria and was shown to synthesize selenophosphate, the active selenium donor. However, mammals have two SPS paralogues, which are designated SPS1 and SPS2. Although it is known that SPS2 catalyses the synthesis of selenophosphate, the function of SPS1 remains largely unclear. To examine the role of SPS1 in mammals, we generated a Sps1-knockout mouse and found that systemic SPS1 deficiency led to embryos that were clearly underdeveloped by embryonic day (E)8.5 and virtually resorbed by E14.5. The knockout of Sps1 in the liver preserved viability, but significantly affected the expression of a large number of mRNAs involved in cancer, embryonic development and the glutathione system. Particularly notable was the extreme deficiency of glutaredoxin 1 (GLRX1) and glutathione transferase Omega 1 (GSTO1). To assess these phenotypes at the cellular level, we targeted the removal of SPS1 in F9 cells, a mouse embryonal carcinoma (EC) cell line, which affected the glutathione system proteins and accordingly led to the accumulation of hydrogen peroxide in the cell. Furthermore, we found that several malignant characteristics of SPS1-deficient F9 cells were reversed, suggesting that SPS1 played a role in supporting and/or sustaining cancer. In addition, the overexpression of mouse or human GLRX1 led to a reversal of observed increases in reactive oxygen species (ROS) in the F9 SPS1/GLRX1-deficient cells and resulted in levels that were similar to those in F9 SPS1-sufficient cells. The results suggested that SPS1 is an essential mammalian enzyme with roles in regulating redox homoeostasis and controlling cell growth.
authors.affiliation: Molecular Biology of Selenium, Mouse Cancer Genetics Program, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, U.S.A.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Tobe
authors.affiliation: Molecular Biology of Selenium, Mouse Cancer Genetics Program, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, U.S.A.
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Carlson
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Jang Hoe
authors.initials: JH
authors.lastname: Huh
authors.affiliation: Tumor Growth Factor Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, U.S.A.
authors.forename: Nadia P
authors.initials: NP
authors.lastname: Castro
authors.affiliation: Molecular Biology of Selenium, Mouse Cancer Genetics Program, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, U.S.A.
authors.forename: Xue-Ming
authors.initials: XM
authors.lastname: Xu
authors.affiliation: Department of Biological Sciences, Towson University, Towson, MD 21252, U.S.A.
authors.forename: Petra A
authors.initials: PA
authors.lastname: Tsuji
authors.affiliation: Division of Genetics, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, U.S.A.
authors.forename: Sang-Goo
authors.initials: SG
authors.lastname: Lee
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Jeyoung
authors.initials: J
authors.lastname: Bang
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Ji-Woon
authors.initials: JW
authors.lastname: Na
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Young-Yun
authors.initials: YY
authors.lastname: Kong
authors.affiliation: Molecular Biology of Selenium, Mouse Cancer Genetics Program, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, U.S.A.
authors.forename: Daniel
authors.initials: D
authors.lastname: Beaglehole
authors.affiliation: Basic Science Program, SAIC-Frederick, NCI-Frederick, Frederick, MD 21702, U.S.A.
authors.forename: Eileen
authors.initials: E
authors.lastname: Southon
authors.affiliation: Nutritional Science Research Group, National Cancer Institute, Rockville, MD 20892, U.S.A.
authors.forename: Harold
authors.initials: H
authors.lastname: Seifried
authors.affiliation: Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, U.S.A.
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.affiliation: Tumor Growth Factor Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, U.S.A.
authors.forename: David S
authors.initials: DS
authors.lastname: Salomon
authors.affiliation: Institut für Biochemie und Molekularbiologie, Rheinische Friedrich-Wilhelms-Universität Bonn, 53115 Bonn, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schweizer
authors.affiliation: Division of Genetics, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, U.S.A.
authors.forename: Vadim N
authors.initials: VN
authors.lastname: Gladyshev
authors.affiliation: Molecular Biology of Selenium, Mouse Cancer Genetics Program, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, U.S.A. hatfield@mail.nih.gov imbglmg@snu.ac.kr.
authors.forename: Dolph L
authors.initials: DL
authors.lastname: Hatfield
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 151-742, Korea hatfield@mail.nih.gov imbglmg@snu.ac.kr.
authors.forename: Byeong Jae
authors.initials: BJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D002460:Cell Line; D054477:Glutaredoxins / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism*; D011732:Pyridoxal Phosphate / Q000378:metabolism
chemical_list: C516006:Glrx protein, mouse; D054477:Glutaredoxins; D011732:Pyridoxal Phosphate; D010770:Phosphotransferases; C062762:selenophosphate synthetase; D005978:Glutathione; D019803:Glutathione Disulfide
keywords: cancer; reactive oxygen species (ROS); redox regulation; selenium; selenocysteine; selenophosphate synthetase 1