Abstract
The human AP-endonuclease (APE1/Ref-1), an essential multifunctional protein, plays a central role in the repair of oxidative base damage via the DNA base excision repair (BER) pathway. The mammalian AP-endonuclease (APE1) overexpression is often observed in tumor cells, and confers resistance to various anticancer drugs; its downregulation sensitizes tumor cells to those agents via induction of apoptosis. Here we show that wild type (WT) but not mutant p53 negatively regulates APE1 expression. Time-dependent decrease was observed in APE1 mRNA and protein levels in the human colorectal cancer line HCT116 p53(+/+), but not in the isogenic p53 null mutant after treatment with camptothecin, a DNA topoisomerase I inhibitor. Furthermore, ectopic expression of WTp53 in the p53 null cells significantly reduced both endogenous APE1 and APE1 promoter-dependent luciferase expression in a dose-dependent fashion. Chromatin immunoprecipitation assays revealed that endogenous p53 is bound to the APE1 promoter region that includes a Sp1 site. We show here that WTp53 interferes with Sp1 binding to the APE1 promoter, which provides a mechanism for the downregulation of APE1. Taken together, our results demonstrate that WTp53 is a negative regulator of APE1 expression, so that repression of APE1 by p53 could provide an additional pathway for p53-dependent induction of apoptosis in response to DNA damage.
| Original language | English |
|---|---|
| Pages (from-to) | 1555-1566 |
| Number of pages | 12 |
| Journal | Nucleic Acids Research |
| Volume | 36 |
| Issue number | 5 |
| DOIs | |
| State | Published - Mar 2008 |
Bibliographical note
Funding Information:We acknowledge the help of Dr D. Bocangel for this study and we thank Dr D. Konkel for critically editing the manuscript. This work was funded by National Institute of Health (R01 ES08457, R01 CA53791 to S.M. and CA98664 to T.I.), American Heart Association grant (AHA#0565008Y to K.B.). Amira Zaky was supported by a Government of Egypt scholarship for research at University of Texas medical Branch. Funding to pay the Open Access publication charges were waived by Oxford University Press.
Funding
We acknowledge the help of Dr D. Bocangel for this study and we thank Dr D. Konkel for critically editing the manuscript. This work was funded by National Institute of Health (R01 ES08457, R01 CA53791 to S.M. and CA98664 to T.I.), American Heart Association grant (AHA#0565008Y to K.B.). Amira Zaky was supported by a Government of Egypt scholarship for research at University of Texas medical Branch. Funding to pay the Open Access publication charges were waived by Oxford University Press.
| Funders | Funder number |
|---|---|
| Government of Egypt | |
| Italian National Health Institute | R01 CA53791, R01 ES08457, CA98664 |
| National Childhood Cancer Registry – National Cancer Institute | R01CA053791 |
| American Heart Association | |
| American Historical Association | 0565008Y |
| University of Texas Medical Branch |
ASJC Scopus subject areas
- Genetics
