Retinoic acid (RA) plays an important role in the regulation of keratinocyte growth, differentiation, and senescence; however, the detailed mechanisms of RA regulation are still unclear. To investigate whether all-trans RA extends the in vitro lifespan of normal human epidermal keratinocytes (NHEKs) by affecting mitotic capacity and/or senescence, we studied the effects of all-trans RA on cell growth, senescence, the expression of βig-h3 and Rb cell cycle regulators, and the telomerase activity of NHEKs after RA exposure. When primary NHEKs were cultured in medium containing 1 nM of all-trans RA, the proliferation and replicative senescence of the cells was significantly stimulated and inhibited, respectively, and the in vitro lifespan of the cells increased 1.4- to 1.5-fold compared to the vehicle control. The levels of βig-h3 and p16 in 1 nM of RA-treated cells remained significantly lower than that of the vehicle control at all population doublings. All-trans RA also triggered induction of telomerase activity in NHEKs with increasing a population doublings induced by RA treatment. These results support that the ability of all-trans RA to postpone, but not prevent, senescence may be related to both partial inhibition of p16 and βig-h3 expression and induction of telomerase activity.

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