Redox state changes in density-dependent regulation of proliferation.

The ability of certain transcription factors to bind to DNA has been demonstrated to be influenced by the redox environment. Therefore, fluctuations in the redox state of the cell may regulate the transcription of genes which control proliferation. To assess whether changes in the redox state may be related to proliferation, levels of oxidized (GSSG) and reduced (GSH) glutathione, the primary modulators of the redox state, were measured in cultures of varying densities of normal human fibroblasts which exhibit contact inhibition of proliferation, as well as fibrosarcoma cells, which lack this mechanism of growth control. Redox potentials calculated from normal, proliferating fibroblasts were found to be -34 mV more reducing than confluent, contact-inhibited cells. However, fibrosarcoma cells did not demonstrate this modulation in redox state. Further, to delineate whether these redox changes were the consequence or the cause of contact inhibition, cultures of subconfluent proliferating fibroblasts were treated with modulators of glutathione synthesis. Buthionine sulfoximine, an inhibitor of GSH synthesis, induced a less reducing redox state and decreased proliferation. In contrast, GSH synthesis precursors caused a more reduced redox state and increased proliferation. Collectively, these results suggest an interrelationship between redox state and growth control.