The plant isoflavenoid genistein activates p53 and Chk2 in an ATM-dependent manner

Genistein is an isoflavenoid that is abundant in soy beans. Genistein has b een reported to have a wide range of biological activities and to play a ro le in the diminished incidence of breast cancer in populations that consume a soy-rich diet. Genistein was originally identified as an inhibitor of ty rosine kinases; however, it also inhibits topoisomerase II by stabilizing t he covalent DNA cleavage complex, an event predicted to cause DNA damage. T he topoisomerase II inhibitor etoposide acts in a similar manner. Here we s how that genistein induces the up-regulation of p53 protein, phosphorylatio n of p53 at serine 15, activation of the sequence-specific DNA binding prop erties of p53, and phosphorylation of the hCds1/Chk2 protein kinase at thre onine 68. Phosphorylation and activation of p53 and phosphorylation of Chk2 were not observed in ATM-deficient cells. In contrast, the topoisomerase I I inhibitor etoposide induced phosphorylation of p53 and Chk2 in ATM-positi ve and ATM-deficient cells. In addition, genistein-treated ATM-deficient ce lls were significantly more susceptible to genistein-induced killing than w ere ATM-positive cells. Together our data suggest that ATM is required for activation of a DNA damage-induced pathway that activates p53 and Chk2 in r esponse to genistein.