Selenophosphate Synthetase 1 is an Essential Protein with Roles in Regulation of Redox Homeostasis and in Malignancy in Mouse Cells

Abstract

Selenophosphate is the active donor of selenium in the biosynthesis of selenocysteine (Sec), which is the 21st amino acid in the genetic code, and is synthesized from selenium and ATP by selenophosphate synthetase (SPS). In higher eukaryotes, there are two isoforms of SPS, SPS1 and SPS2. SPS2 catalyzes the synthesis of selenophosphate, while the function of SPS1 is largely unknown. To examine the role of SPS1 in mammals, we targeted the removal of SPS1 in F9 cells, a mouse embryonal carcinoma cell line, which led to growth retardation similarly as previously observed in SPS1‐deficient Drosophila and human cells. Transcriptome analysis showed that SPS1 deficiency significantly affected expression of a large number of mRNAs involved in cancer, embryonic development and the glutathione system. Particularly, the levels of glutaredoxin 1 (GLRX1) and glutathione‐S‐transferase omega 1 were extremely decreased. As expected from the change in gene expression pattern, reactive oxygen species (ROS) were accumulated, and malignant cancer properties (e.g., cell invasion and foci formation) were inhibited by SPS1 deficiency. Interestingly, overexpression of human GLRX1 in SPS1 deficient F9 cells reversed those phenotypes (ROS accumulation and retardation of cell invasion) induced by SPS1 knockdown. Our results suggest that SPS1 is an essential mammalian enzyme with roles in regulating redox homeostasis and controlling cell growth.