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Role of p53 in aziridinylbenzoquinone-induced p21waf1 expression
R C Wu1, A Hohenstein, J M Park
1Department of Molecular Microbiology and Immunology, School of Medicine and K Norris Jr. Comprehensive Cancer Center, University of Southern California, Los Angeles 90033, USA.
Abstract:
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.
Insights
The anticancer drug DZQ increases p21 protein expression, a cell cycle inhibitor. This effect depends on the tumor suppressor p53, suggesting a key role for the p53-p21 pathway in DZQ
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Quinones are a major class of anticancer drugs, but their precise mechanisms remain unclear.
- The quinone compound 3,6-diaziridinyl-1,4-benzoquinone (DZQ) increases p21waf1/cip1/sdi1 protein, a cyclin-dependent kinase inhibitor.
- p21 is a critical negative regulator of the cell cycle.
Purpose of the Study:
- To investigate the molecular mechanisms underlying p21 induction by DZQ.
- To determine the role of the p53 tumor suppressor protein in DZQ-mediated p21 expression.
- To assess the impact of p53 status on cellular sensitivity to DZQ.
Main Methods:
- Investigated p21 induction by DZQ in cells with varying p53 functional status.
- Utilized gene introduction to restore wild-type p53 in p53-negative cells.
- Assessed the sensitivity of HL60 myeloid leukemia cells to DZQ following p53 restoration.
Main Results:
- DZQ-induced p21 expression is regulated transcriptionally and requires p53 activation.
- p53-negative cells exhibit significantly diminished DZQ-mediated p21 induction.
- Restoring wild-type p53 in p53-deficient cells re-establishes strong p21 inducibility by DZQ.
- Wild-type p53 status enhances the cytotoxic effects of DZQ in HL60 cells.
Conclusions:
- The p53-p21 pathway is crucial for the gene-regulatory effects of aziridinylbenzoquinones like DZQ.
- p53 activation mediates the transcriptional induction of p21 by DZQ.
- The p53-p21 pathway plays a central role in mediating the cytotoxic actions of aziridinylbenzoquinones.