Potassium-chloride cotransporter mediates cell cycle progression and proliferation of human corneal epithelial cells

José E. Capó-Aponte, Zheng Wang, M. A.Murat Akinci, J. Mario Wolosin, Kathryn S. Pokorny, Pavel Iserovich, Peter S. Reinach

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Epidermal growth factor (EGF)-induced proliferation of corneal epithelial cells contributes to its renewal, which maintains the protective and refractive properties of the cornea. This study characterized in human corneal epithelial cells (HCEC) the role of the potassium-chloride cotransporter (KCC) in mediating (1) EGF-induced mitogen-activated protein kinase (MAPK) pathway activation; (2) increases in cell cycle progression; and (3) proliferation. The KCC inhibitor [(dihydroindenyl)oxy] alkanoic acid (DIOA) and KCC activator N-ethylmaleimide (NEM), suppressed and enhanced EGF-induced p44/42MAPK activation, respectively. Such selective modulation was mirrored by corresponding changes in cell proliferation and shifts in cell cycle distribution. DIOA induced a 20% increase in G0/G1-phase cell population, whereas NEM induced a 22% increase in the proportion of cells in the G2/M-phase and accelerated the transition from G0/G1-phase to the S-phase. Associated with these changes, KCC1 content in a plasma membrane enriched fraction increased by 300%. Alterations in regulatory volume capacity were associated with corresponding changes in both KCC1 membrane content and activity. These results indicate that EGF-induced increases in KCC1 activity and content modulate cell volume changes required for (1) activation of the p44/42MAPK signaling pathway, (2) cell cycle progression, and (3) increases in cell proliferation.

Original languageEnglish
Pages (from-to)2709-2718
Number of pages10
JournalCell Cycle
Issue number21
StatePublished - 1 Nov 2007


  • Cell cycle
  • Cell proliferation
  • EGF
  • Human corneal epithelial cells
  • Hypotonic challenge
  • KCC
  • Regulatory volume decrease
  • p38MAPK
  • p44/42MAPK


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