DIFFERENTIAL CELL-CYCLE CHECKPOINT RESPONSE IN NORMAL HUMAN KERATINOCYTES AND FIBROBLASTS

The incidence of DNA mutation and subsequent risk of transformation in different cell types may depend on cell type-specific variation in po sition and duration of cell cycle arrest after exposure to DNA-damagin g agents. To determine whether cell type-specific checkpoints occur, n ormal human epidermal keratinocytes (HKs) and human dermal fibroblasts (HFs), isolated from the same tissue, were exposed to genotoxic agent s. Following exposure, cell cycle arrest profiles, cell proliferation rates, and select protein levels and activities were analyzed and foun d to be cell type dependent, After exposure to either gamma-radiation or Adriamycin, HFs arrested primarily in G(1), whereas HKs arrested pr edominantly in G(2). The attenuated G(1) arrest in the HKs correlated with less p53 protein accumulation, as compared to that observed in G( 1)-arrested HFs. Although gamma-irradiated HFs were unable to reenter the cell cycle, HKs began proliferating 72 h posttreatment. Consistent with the cell cycle profiles observed, cyclin-dependent kinase activi ties were inhibited for a longer duration in HFs as compared to HKs af ter gamma-irradiation. The results indicate that cell cycle checkpoint response to genotoxic insult may vary according to cell type within a ny given tissue. The attenuated G(1) arrest observed in HKs may be an important factor in the transforming events leading to skin neoplasia.