Osmotic Stress-induced Phosphorylation of H2AX by Polo-like-kinase 3 Affects Cell Cycle Progression in Human Corneal Epithelial Cells [Cell Biology]

September 8th, 2014 by Wang, L., Dai, W., Lu, L.

Increased concentration of extracellular solutes affects cell function and fate by stimulating cellular responses, such as evoking MAPK cascades, altering cell cycle progression and causing apoptosis. Our study results here demonstrate that hyperosmotic stress-induced H2AX phosphorylation (γH2AX) by an unrevealed kinase cascade involving polo-like kinase 3 (Plk3) in human corneal epithelial (HCE) cells. We found that hyperosmotic stress induced DNA-double strand breaks and increased γH2AX in HCE cells. Phosphorylation of H2AX at serine 139 was catalyzed by hyperosmotic stress-induced activation of Plk3. Plk3 directly interacted with H2AX and was co-localized with γH2AX in nuclei of hyperosmotic stress-induced cells. Suppression of Plk3 activity by overexpression of a kinase-silencing mutant or by knocking down Plk3 mRNA effectively reduced γH2AX in hyperosmotic stress-induced cells. This was consistent with results that γH2AX was markedly suppressed in Plk3-/- knockout mouse corneal epithelial layer in response to hyperosmotic stimulation. The effect of hyperosmotic stress-activated Plk3 and increased γH2AX on cell cycle progression showed an accumulation of G2/M phase, altered population in G1 and S phases and increased apoptosis. Our results for the first time reveal that hyperosmotic stress-activated Plk3 elicited γH2AX. This Plk3-mediated activation of γH2AX subsequently regulates the cell cycle progression and cell fate.
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