A mammalian monothiol glutaredoxin, Grx3, is critical for cell cycle progression during embryogenesis

Ning Hui Cheng, Wei Zhang, Wei Qin Chen, Jianping Jin, Xiaojiang Cui, Nancy F. Butte, Lawrence Chan, Kendal D. Hirschi

Research output: Contribution to journalArticle

38 Scopus citations

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 G2/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. Structured digital abstract and by Mammalian monothiol Grx3 is able to rescue growth defects of yeast mutant grx3grx4 cells and to protect cells against oxidative stress. Disruption of Grx3 causes early embryo death. Mouse embryonic fibroblasts from Grx3 null mice display impaired growth and cell cycle progression at the G2/M phase. The defective cell cycle progression during late mitosis may account for early embryonic lethality.

Original languageEnglish (US)
Pages (from-to)2525-2539
Number of pages15
JournalFEBS Journal
Volume278
Issue number14
DOIs
StatePublished - Jul 2011

Keywords

  • cell cycle
  • embryogenesis
  • glutaredoxin
  • mouse
  • oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Cheng, N. H., Zhang, W., Chen, W. Q., Jin, J., Cui, X., Butte, N. F., Chan, L., & Hirschi, K. D. (2011). A mammalian monothiol glutaredoxin, Grx3, is critical for cell cycle progression during embryogenesis. FEBS Journal, 278(14), 2525-2539. https://doi.org/10.1111/j.1742-4658.2011.08178.x