Robust p53 phenotypes and prospective downstream targets in telomerase-immortalized human cells.

Cancers that retain wild type presumably harbor other clonal alterations that permitted their precursors to bypass p53-mediated growth suppression. Consequently, studies that employ -wild type cancer cells and their isogenic derivatives may systematically fail to appreciate the full scope of p53 functionality. Several phenotypes are known to be absent in the widely used isogenic HCT116 colorectal cancer (CRC) model, which originated from a tumor that had retained wild type . In contrast, we show that restoration of p53 in the -mutant CRC cell line DLD-1 impeded cell proliferation, increased levels of senescence and sensitized cells to ionizing radiation (IR). To study p53 in a non-cancer context, we disrupted in hTERT-RPE1 cells. Derived from primary cells that were immortalized , hTERT-RPE1 expressed striking p53-dependent phenotypes and appeared to select for p53 loss during routine culture. hTERT-RPE1 expressed a p53-responsive transcriptome that was highly representative of diverse experimental systems. We discovered several novel downstream p53 targets of potential clinical relevance including , which is involved in the detoxification of aldehydes and the metabolism of reactive oxygen species, and () which encodes a secreted surface protein that is overexpressed in many tumors.