IFN-gamma Induction of p21WAF1 Is Required for Cell Cycle Inhibition and Suppression of Apoptosis

Interferons (IFN) inhibit the growth of tumor cells by blocking the progression of their cell cycle. Recently, we showed that this cell cycle inhibition correlates with the ability of IFN to upregulate the cyclin-dependent kinase inhibitor p21WAF1. This, however, is not proof of a causal relationship. Using p21WAF1-deficient cells derived from the HCT116 colon adenocarcinoma cell line, we now show that p21W A F1 is indeed responsible for the antiproliferative effects of the type II IFN, IFN-gamma. IFN-gamma upregulated p21W A F1 expression in a p53-independent manner, decreased cyclin-dependent kinase 2 activity, and inhibited entry into the S phase of the cell cycle in p21+/+ but not in p21-/-HCT116 cells. We additionally found that the lack of p21WAF1 expression resulted in an increase in the ability of IFN-gamma to induce apoptosis, as reflected by an earlier induction of DNA fragmentation and caspase 3 activity in p21-/-cell. Our results indicate that p21WAF1 expression is necessary for IFN-gamma-mediated cell cycle inhibition and suppression of IFN-gamma-induced apoptosis.