Inhibition of <scp>G</scp>₁ cell cycle arrest in human gingival fibroblasts exposed to phenytoin

<jats:title>Abstract</jats:title><jats:p>Gingival overgrowth is caused in response to the antiepileptic drug phenytoin (<jats:styled-content style="fixed-case">PHT</jats:styled-content>). <jats:styled-content style="fixed-case">PHT</jats:styled-content>‐induced gingival overgrowth is characterized by the proliferation of fibroblasts and increased collagen formation in gingiva. Fibroblast proliferation is regulated through the cell cycle. Thus, in the present study, we examined the effects of <jats:styled-content style="fixed-case">PHT</jats:styled-content> on the cell cycle, the expression of cell cycle control proteins and the proliferation in human gingival fibroblasts (<jats:styled-content style="fixed-case">hGF</jats:styled-content>s). Cells were stimulated in serum‐free <jats:styled-content style="fixed-case">DMEM</jats:styled-content> with or without 0.25 μ<jats:sc>m </jats:sc><jats:styled-content style="fixed-case">PHT</jats:styled-content>. Subsequently, the cell cycle phase distribution and the protein expression after 24 h and the cell proliferation after 24, 48 and 72 h were evaluated. <jats:styled-content style="fixed-case">PHT</jats:styled-content> significantly inhibited synchronization at the <jats:styled-content style="fixed-case">G</jats:styled-content><jats:sub>0</jats:sub>/<jats:styled-content style="fixed-case">G</jats:styled-content><jats:sub>1</jats:sub> phase of the cell cycle in <jats:styled-content style="fixed-case">hGF</jats:styled-content>s through serum starvation. Stimulation with <jats:styled-content style="fixed-case">PHT</jats:styled-content> for 48 and 72 h significantly induced a proliferative response in <jats:styled-content style="fixed-case">hGF</jats:styled-content>s. <jats:styled-content style="fixed-case">PHT</jats:styled-content> decreased the expression of the <jats:styled-content style="fixed-case">C</jats:styled-content>dk‐inhibitory proteins p21 and p27 and increased the levels of the <jats:styled-content style="fixed-case">S</jats:styled-content> phase‐promoting proteins phospho‐Thr160‐<jats:styled-content style="fixed-case">C</jats:styled-content>dk2 and phospho‐<jats:styled-content style="fixed-case">S</jats:styled-content>er807/811‐<jats:styled-content style="fixed-case">R</jats:styled-content>b in serum‐free <jats:styled-content style="fixed-case">DMEM</jats:styled-content>. The inhibition of <jats:styled-content style="fixed-case">G</jats:styled-content><jats:sub>1</jats:sub> cell cycle arrest in <jats:styled-content style="fixed-case">hGF</jats:styled-content>s may result from an increase in phosphorylated <jats:styled-content style="fixed-case">C</jats:styled-content>dk2 and <jats:styled-content style="fixed-case">R</jats:styled-content>b proteins and decreased levels of p21 and p27 proteins by <jats:styled-content style="fixed-case">PHT</jats:styled-content>. The gingival overgrowth may be caused by the failure of the G1 cell cycle arrest in GFs exposed to <jats:styled-content style="fixed-case">PHT</jats:styled-content>.</jats:p>