Role of p53 in aziridinylbenzoquinone-induced p21waf1 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 shown earlier that the quinone 3,6-diaziridinyl-1,4-benzoquinone (DZQ) leads to the increased expression of p21waf1/cip1/sdi1 protein, an inhibitor of cyclin-dependent kinases. Because p21 has been established as an important negative regulator of the cell cycle, we further investigated 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 cells that lack functional p53 protein, DZQ-mediated p21 induction is greatly diminished. However, the introduction of a wild type p53 gene into p53-negative cells restores the strong DZQ-inducibility of p21. Restoration of wild type p53 status in HL60 myeloid leukemia cells significantly increases the cells' sensitivity to the cytotoxic effects of DZQ. Thus, our results indicate that the p53-p21 pathway may play a central role in mediating the gene-regulatory and cytotoxic effects of aziridinylbenzoquinones.
Department of Molecular Microbiology and Immunology, School of Medicine and K Norris Jr. Comprehensive Cancer Center, University of Southern California, Los Angeles 90033, USA.
R C
RC
Wu
A
A
Hohenstein
J M
JM
Park
X
X
Qiu
S
S
Mueller
E
E
Cadenas
A H
AH
Schönthal
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001388:Aziridines / Q000494:pharmacology*; D001483:Base Sequence; D016227:Benzoquinones / Q000494:pharmacology*; D001665:Binding Sites; D001943:Breast Neoplasms; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis; D051379:Mice; D012516:Osteosarcoma; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000970:Antineoplastic Agents; D001388:Aziridines; D016227:Benzoquinones; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; C009970:ethylenimine quinone; D008156:Luciferases