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 been reported to have a wide range of biological activities and to play a role in the diminished incidence of breast cancer in populations that consume a soy-rich diet. Genistein was originally identified as an inhibitor of tyrosine kinases; however, it also inhibits topoisomerase II by stabilizing the covalent DNA cleavage complex, an event predicted to cause DNA damage. The topoisomerase II inhibitor etoposide acts in a similar manner. Here we show that genistein induces the up-regulation of p53 protein, phosphorylation of p53 at serine 15, activation of the sequence-specific DNA binding properties of p53, and phosphorylation of the hCds1/Chk2 protein kinase at threonine 68. Phosphorylation and activation of p53 and phosphorylation of Chk2 were not observed in ATM-deficient cells. In contrast, the topoisomerase II inhibitor etoposide induced phosphorylation of p53 and Chk2 in ATM-positive and ATM-deficient cells. In addition, genistein-treated ATM-deficient cells were significantly more susceptible to genistein-induced killing than were 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 response to genistein.
Ye
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R
Department of Biological Sciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
Bodero
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A
Zhou
B B
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Khanna
K K
KK
Lavin
M F
MF
Lees-Miller
S P
SP
D000730:Androstadienes / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D016227:Benzoquinones; D002110:Caffeine / Q000494:pharmacology; D018797:Cell Cycle Proteins; D002460:Cell Line; D064447:Checkpoint Kinase 2; D053938:DNA Fragmentation; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D047029:Lactams, Macrocyclic; D009154:Mutation; D010766:Phosphorylation; D010946:Plants, Medicinal; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D000077191:Wortmannin
D000730:Androstadienes; D016227:Benzoquinones; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D011809:Quinones; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D017828:Rifabutin; D002110:Caffeine; D005047:Etoposide; C020754:herbimycin; D019833:Genistein; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; D011505:Protein-Tyrosine Kinases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; D000077191:Wortmannin