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Figure 3. Schematic diagram shows that inactivation of p16INK4a in early passage primary human keratinocyte cultures (bearing holoclones) is per se sufficient to induce cellular immortalization by impairing keratinocyte clonal evolution and maintaining cells in stem cell compartment. Inactivation of p16INK4a in late-passage primary human keratinocyte cultures (depleted in holoclones) does not affect clonal evolution, and onset of senescence is anyway triggered. Similar findings are obtained when overexpressing p16INK4a in early passage primary human keratinocytes.