Fig. 5.

Endothelial cell cycle responses under physiological and GSH-deficient states. During cell proliferation, cytosol-to-nuclear GSH transport is increased under physiological GSH conditions. An increase in intra-nuclear reducing environment promotes gene transcription that brings about normal cell cycle progression wherein DNA synthesis occurs during the S-phase. Normal nuclear cdk1expression controls S-to-G2-to-M cell transition. Decreased cytosolic GSH due to inhibition of synthesis or enhanced oxidative stress results in decreased nuclear GSH import. Low nuclear GSH induces a DNA damage response, presumably due to increased oxidative DNA damage. An increase in chk-2 activation (increased p-chk2) and nuclear GAPDH accumulation contributes to a prolongation of the S-phase and a delay in cell cycle progression. In part, increased p-chk2 promotes the retention of cdk1 in the cytosol; a decrease in nuclear cdk1 delays the S-to-G2-to-M transition. Significantly, the lengthening of the S-phase allows for extended time for DNA repair.