Location: Children's Nutrition Research Center
Title: A mammalian monothiol glutaredoxin, Grx3, is critical for cell cycle progression during embryogenesis Authors
|Cheng, Ning-Hui -|
|Zhang, Wei -|
|Chen, Wei-Qin -|
|Jin, Jianping -|
|Cui, Xiaojiang -|
|Butte, Nancy -|
|Chan, Lawrence -|
|Hirschi, Kendal -|
Submitted to: FEBS Journal
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: February 1, 2011
Publication Date: July 1, 2011
Citation: Cheng, N., 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. Interpretive Summary: Too much reactive oxygen species (ROS) within the cells could cause damage and eventually cell death. For this reason, cells usually tightly regulate ROS levels using various antioxidant proteins and one of which is the protein called glutaredoxin. This new study conducted by the Scientists at the Children Nutrition Research Center demonstrated that one type of glutaredoxins, Grx3, is crucial for early embryo development in mice. When Grx3 is absent, the young embryos stop growth and die before the pregnant mice give birth due to high levels of toxic oxygen species accumulated in the cells. Thus, this study provides insights onto the effect of oxidative stress on embryo growth and development and also a good animal model to further investigate, at the molecular level, the cause of birth defects in human.
Technical 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. Structured digital abstract / MmGRX3 and ScGRX3 colocalize by fluorescence microscopy (View interaction).