IFN-gamma induction of p21(WAF1) is required for cell cycle inhibition andsuppression of apoptosis

Interferons (IFN) inhibit the growth of tumor cells by blocking the progres sion of their cell cycle. Recently, we showed that this cell cycle inhibiti on correlates with the ability of IFN to upregulate the cyclin-dependent ki nase inhibitor p21(WAF1). This, however, is not proof of a causal relations hip. Using p21(WAF1)-deficient cells derived from the HCT116 colon adenocar cinoma cell line, we now show that p21(WAF1) is indeed responsible for the antiproliferative effects of the type II IFN, IFN-gamma, IFN-gamma upregula ted p21(WAF1) expression in a p53-independent manner, decreased cyclin-depe ndent kinase 2 activity, and inhibited entry into the S phase of the cell c ycle in p21(+/+) but not in p21(-/-) HCT116 cells, We additionally found th at the lack of p21(WAF1) expression resulted in an increase in the ability of IFN-gamma to induce apoptosis, as reflected by an earlier induction of D NA fragmentation and caspase 3 activity in p21(-/-) cell. Our results indic ate that p21WAF1 expression is necessary for IFN-gamma-mediated cell cycle inhibition and suppression of IFN-gamma-induced apoptosis.