Normal and c-Myc-promoted human keratinocyte differentiation both occur via a novel cell cycle involving cellular growth and endoreplication.

The relationship between cell cycle and differentiation in human keratinocytes is poorly understood. It is believed that keratinocytes suppress DNA replication and cell cycle arrest in G0 before they initiate terminal differentiation. However, a temporal separation between both events has not been established. Moreover, c-Myc promotes keratinocyte differentiation without causing cell cycle arrest. To address these paradoxes we have analysed cell cycle control during normal and c-Myc-promoted differentiation. Continuous activation of c-Myc or initiation of terminal differentiation results in a block of G2/M, cellular growth, endoreplication and polyploidy. Keratinocytes abandon G1, continue replicating DNA as they differentiate terminally and become polyploid. In fact, simply blocking mitosis with nocodazole resulted in increased cell size, terminal differentiation and endoreplication. This indicates that terminal differentiation associates with defective cell cycle progression and provides a novel insight into c-Myc biology.