AUTOCRINE EFFECT OF OXYGEN ON CELL PROLIFERATION

Abstract

We report the first evidence that oxygen tension regulates the synthesis of a protein with growth-promoting activity in human fibroblasts. Sparse cultures of embryonic fibroblasts were synchronized in the G₀ portion of the cell cycle by serum starvation and then placed under either low (2.5%) or ambient (20%) oxygen for 24 hours. When serum was added to induce proliferation, the number of cells that initiated DNA synthesis was ten-fold greater in 2.5% than in 20% oxygen. Oxygen concentration did not affect the latent period for DNA synthesis. Exposure to 2.5% oxygen during G₀ was sufficient to increase DNA synthesis. Oxygen also affected the mitogenic response to purified growth factors. Placing fibroblasts in 2.5% oxygen during G₀ increased their mitogenic response to epidermal growth factor six-fold. For insulin-like growth factor 1 and platelet-derived growth factor, the increases were two-and six-fold, respectively.

To understand how oxygen regulates cell proliferation at the level of gene expression, we harvested medium conditioned by G₀ fibroblasts under 2.5% oxygen. This conditioned medium increased the mitogenic effect of epidermal growth factor on cells under 20% oxygen. This medium did not stimulate proliferation in the absence of added growth factor. Proteases abolished the activity of this conditioned medium. We conclude that reducing oxygen concentration below that of the ambient air induces fibroblasts to synthesize and secrete a protein with growth-promoting activity. This protein appears to enhance the mitogenic response to growth factors and may act by altering either receptors or intracellular mediators of the growth response.

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