ROLE OF P53 IN AZIRIDINYLBENZOQUINONE-INDUCED P21(WAF1) EXPRESSION

Quinones are the second largest family of anticancer drugs clinically used in the United States. However, their exact mode of action at the cellular and molecular level is not completely understood. We have sho wn earlier that the quinone 3,6-diaziridinyl-1,4-benzoquinone (DZQ) le ads to the increased expression of p21(waf1/cip/sdi1) protein, an inhi bitor of cyclin-dependent kinases, Because p21 has been established as an important negative regulator of the cell cycle, we further investi gated the molecular basis of p21 induction by DZQ. Here we report that the induction of p21 by DZQ is regulated at the transcriptional level , and requires the activation of p53, a tumor suppressor protein. In c ells that lack functional p53 protein, DZQ-mediated p21 induction is g reatly diminished. However, the introduction of a wild type p53 gene i nto p53-negative cells restores the strong DZQ-inducibility of p21. Re storation of wild type p53 status in HL60 myeloid leukemia cells signi ficantly increases the cells' sensitivity to the cytotoxic effects of DZQ. Thus, our results indicate that the p53-p21 pathway may play a ce ntral role in mediating the gene-regulatory and cytotoxic effects of a ziridinylbenzoquinones.