title: A mammalian monothiol glutaredoxin, Grx3, is critical for cell cycle progression during embryogenesis.
abstract: Glutaredoxins (Grxs) have been shown to be critical in maintaining redox homeostasis in living cells. Recently, an emerging subgroup of Grxs with one cysteine residue in the putative active motif (monothiol Grxs) has been identified. However, the biological and physiological functions of this group of proteins have not been well characterized. Here, we characterize a mammalian monothiol Grx (Grx3, also termed TXNL2/PICOT) with high similarity to yeast ScGrx3/ScGrx4. In yeast expression assays, mammalian Grx3s were localized to the nuclei and able to rescue growth defects of grx3grx4 cells. Furthermore, Grx3 inhibited iron accumulation in yeast grx3gxr4 cells and suppressed the sensitivity of mutant cells to exogenous oxidants. In mice, Grx3 mRNA was ubiquitously expressed in developing embryos, adult tissues and organs, and was induced during oxidative stress. Mouse embryos absent of Grx3 grew smaller with morphological defects and eventually died at 12.5 days of gestation. Analysis in mouse embryonic fibroblasts revealed that Grx3(-/-) cells had impaired growth and cell cycle progression at the G(2) /M phase, whereas the DNA replication during the S phase was not affected by Grx3 deletion. Furthermore, Grx3-knockdown HeLa cells displayed a significant delay in mitotic exit and had a higher percentage of binucleated cells. Therefore, our findings suggest that the mammalian Grx3 has conserved functions in protecting cells against oxidative stress and deletion of Grx3 in mice causes early embryonic lethality which could be due to defective cell cycle progression during late mitosis.
authors.affiliation: United States Department of Agriculture / Agricultural Research Service Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Ning-Hui
authors.initials: NH
authors.lastname: Cheng
authors.affiliation: Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Wei-Qin
authors.initials: WQ
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Jianping
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, CA, USA.
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Cui
authors.affiliation: United States Department of Agriculture / Agricultural Research Service Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Nancy F
authors.initials: NF
authors.lastname: Butte
authors.affiliation: Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.affiliation: United States Department of Agriculture / Agricultural Research Service Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Kendal D
authors.initials: KD
authors.lastname: Hirschi
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002453:Cell Cycle; D002460:Cell Line; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism; D047108:Embryonic Development; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020868:Gene Silencing; D005804:Genes, Lethal; D054477:Glutaredoxins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032446:Myoblasts / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D011490:Protein Disulfide Reductase (Glutathione); D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C404105:GLRX3 protein, human; D054477:Glutaredoxins; D007527:Isoenzymes; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D011490:Protein Disulfide Reductase (Glutathione); C498606:Txnl2 protein, mouse