Central role of p14^ARF in cell cycle regulation.

The central role of p14^ARF in the control of cell cycle in normal cells (A) converts it into a marker of inactivation of multiple cell cycle regulatory pathways (B). Nuclear overexpression as a consequence of multiple molecular alterations involving Rb pathway (inactivation of the Rb pathway generates active E2F-1, which induces transcription of the p14^ARF gene); myc, and viral oncogenes such as E1A or v-abl, which also induce p14^ARF; and alterations in the p53-Hdm2 pathway resulting in disruption of the p53-mediated negative regulation of p14^ARF. Thick arrows indicate events derived from oncogene activation; black crosses represent inactivation of tumor suppressor genes.