Differential responses of SOD1-deficient mouse embryonic fibroblasts to oxygen concentrations

作者：Tsunoda Satoshi; Kibe Noriko; Kurahashi Toshihiro; Fujii Junichi^*

来源：Archives of Biochemistry and Biophysics, 2013, 537(1): 5-11.

DOI：10.1016/j.abb.2013.06.008

• Mouse embryonic fibroblast
• Superoxide dismutase
• Cell cycle
• p53

Superoxide dismutase (SOD) plays a role in antioxidation, and SOD1-knockout (KO) mice show moderate phenotypes. Primary cultured mouse embryonic fibroblasts (MEFs) lead to growth failure and eventual death under normoxic culture (20% oxygen). We attempted to elucidate the molecular mechanisms responsible for the oxygen toxicity in SOD1-KO MEFs. Increases in reactive oxygen species, lipid peroxidation products, and senescence-associated beta-galactosidase activity were observed in SOD1-KO MEFs. Hypoxic culture (2% oxygen) averted immediate cell death but could not recover the proliferative ability of the SOD1-KO cells. The cell cycles of SOD1-deficient MEFs were arrested at the G2 and M phases, leading to the accumulation of tetraploid cells under hypoxic culture. The suppressed expression of cyclin A2 and B1 and the concomitant induction of p21(Waf1) were evident in SOD1-KO cells. The phosphorylation of p53 and histone H2Ax and the induction of the two proapoptotic genes Box and Noxa were evident in SOD1-deficient MEFs and more enhanced under normoxic culture than under hypoxic culture. We concluded that low levels of oxygen consumption moderately activates the p53 pathway, and leads to cellular senescence, but that high levels of oxygen consumption hyperactivates the p53 pathway, which results in cell death in SOD1-deficient MEFs.

• 出版日期2013-9-1