| The Ink4A/ARF locus encodes two tumor suppressor proteins, p16 INK4a and p19ARF (p14ARF in humans). The p19ARF tumor suppressor, which is mutated, deleted, or silenced in a significant number of human cancers, is coupled to the p53 pathway. In response to sustained hyperproliferative signaling, ARF is activated and in turn stabilizes and activates p53 by antagonizing its negative regulator, Mdm2. Activation of the ARF-p53-Mdm2 pathway results in cell cycle arrest or apoptosis and is considered to be a checkpoint that protects cells from tumorigenesis. Observations that ARF retained its ability to cause cell cycle arrest in cells that were p53-/- or p53-/- MDM2-/- and that its reintroduction into p53-/- Mdm2-/- ARF-/- mouse embryonic fibroblasts (MEFs) caused a delayed G1-phase growth arrest suggest that ARF does not only function in the p53 axis.;One target that is regulated by ARF in the absence of p53 is DP1. Through its regulation of DP1, the functional and regulatory partner of E2F, it inhibits E2F1 function and induces cell cycle arrest. I found that ARF regulates both "activator" and "repressor" E2Fs. Through its regulation of the most abundant repressor E2F, E2F4, it stimulates the expression of repair genes such as XPC, UNG2, MSH2 and BRCA1. My research has provided novel findings on how ARF functions as a tumor suppressor in maintaining genomic integrity. |
