MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Karpf, A. R.
Right arrow Articles by Jones, D. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Karpf, A. R.
Right arrow Articles by Jones, D. A.

Vol. 59, Issue 4, 751-757, April 2001

Activation of the p53 DNA Damage Response Pathway after Inhibition of DNA Methyltransferase by 5-Aza-2'-deoxycytidine

Adam R. Karpf, Brent C. Moore, Ted O. Ririe, and David A. Jones

Division of Molecular Pharmacology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah

Transcriptional silencing of tumor suppressor genes by DNA methylation occurs in cancer cell lines and in human tumors. This has led to the pursuit of DNA methyltransferase inhibition as a drug target. 5-Aza-2'-deoxycytidine [5-aza-CdR (decitabine)], a potent inhibitor of DNA methyltransferase, is a drug currently in clinical trials for the treatment of solid tumors and leukemia. The efficacy of 5-aza-CdR may be related to the induction of methylation-silenced tumor suppressor genes, genomic hypomethylation, and/or enzyme-DNA adduct formation. Here, we test the hypothesis that 5-aza-CdR treatment is perceived as DNA damage, as assessed by the activation of the tumor suppressor p53. We show that 1) colon tumor cell lines expressing wild-type p53 are more sensitive to 5-aza-CdR mediated growth arrest and cytotoxicity; 2) the response to 5-aza-CdR treatment includes the induction and activation of wild-type but not mutant p53 protein; and 3) the induction of the downstream p53 target gene p21 is partially p53-dependent. The induction of p53 protein after 5-aza-CdR treatment did not correlate with an increase in p53 transcripts, indicating that hypomethylation at the p53 promoter does not account for the p53 response. It is relevant that 5-aza-CdR has shown the greatest promise in clinical trials for the treatment of chronic myelogenous leukemia, a malignancy in which functional p53 is often retained. Our data raise the hypothesis that p53 activation may contribute to the clinical efficacy and/or toxicity of 5-aza-CdR.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Cancer Res.Home page
P. A. Link, M. R. Baer, S. R. James, D. A. Jones, and A. R. Karpf
p53-Inducible Ribonucleotide Reductase (p53R2/RRM2B) Is a DNA Hypomethylation-Independent Decitabine Gene Target That Correlates with Clinical Response in Myelodysplastic Syndrome/Acute Myelogenous Leukemia
Cancer Res., November 15, 2008; 68(22): 9358 - 9366.
[Abstract] [Full Text] [PDF]

Home page
 haematolHome page
T. Khong, J. Sharkey, and A. Spencer
The effect of azacitidine on interleukin-6 signaling and nuclear factor-{kappa}B activation and its in vitro and in vivo activity against multiple myeloma
Haematologica, June 1, 2008; 93(6): 860 - 869.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. Wang, Y. Zhao, L. Li, M. A. McNutt, L. Wu, S. Lu, Y. Yu, W. Zhou, J. Feng, G. Chai, et al.
An ATM- and Rad3-related (ATR) Signaling Pathway and a Phosphorylation-Acetylation Cascade Are Involved in Activation of p53/p21Waf1/Cip1 in Response to 5-Aza-2'-deoxycytidine Treatment
J. Biol. Chem., February 1, 2008; 283(5): 2564 - 2574.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
S. S. Palii, B. O. Van Emburgh, U. T. Sankpal, K. D. Brown, and K. D. Robertson
DNA Methylation Inhibitor 5-Aza-2'-Deoxycytidine Induces Reversible Genome-Wide DNA Damage That Is Distinctly Influenced by DNA Methyltransferases 1 and 3B
Mol. Cell. Biol., January 15, 2008; 28(2): 752 - 771.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
R. Mabaera, M. R. Greene, C. A. Richardson, S. J. Conine, C. D. Kozul, and C. H. Lowrey
Neither DNA hypomethylation nor changes in the kinetics of erythroid differentiation explain 5-azacytidine's ability to induce human fetal hemoglobin
Blood, January 1, 2008; 111(1): 411 - 420.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
H. K. Kuo, J. D. Griffith, and K. N. Kreuzer
5-Azacytidine Induced Methyltransferase-DNA Adducts Block DNA Replication In vivo
Cancer Res., September 1, 2007; 67(17): 8248 - 8254.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
T. Kiziltepe, T. Hideshima, L. Catley, N. Raje, H. Yasui, N. Shiraishi, Y. Okawa, H. Ikeda, S. Vallet, S. Pozzi, et al.
5-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells
Mol. Cancer Ther., June 1, 2007; 6(6): 1718 - 1727.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
J. Xu, J.-Y. Zhou, M. A. Tainsky, and G. S. Wu
Evidence that Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Induction by 5-Aza-2'-Deoxycytidine Sensitizes Human Breast Cancer Cells to Adriamycin
Cancer Res., February 1, 2007; 67(3): 1203 - 1211.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
G. Egger, A. M. Aparicio, S. G. Escobar, and P. A. Jones
Inhibition of Histone Deacetylation Does Not Block Resilencing of p16 after 5-Aza-2'-Deoxycytidine Treatment
Cancer Res., January 1, 2007; 67(1): 346 - 353.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
F. J. Reu, D. W. Leaman, R. R. Maitra, S. I. Bae, L. Cherkassky, M. W. Fox, D. R. Rempinski, N. Beaulieu, A. R. MacLeod, and E. C. Borden
Expression of RASSF1A, an Epigenetically Silenced Tumor Suppressor, Overcomes Resistance to Apoptosis Induction by Interferons.
Cancer Res., March 1, 2006; 66(5): 2785 - 2793.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
D. R. Hodge, B. Peng, J. C. Cherry, E. M. Hurt, S. D. Fox, J. A. Kelley, D. J. Munroe, and W. L. Farrar
Interleukin 6 Supports the Maintenance of p53 Tumor Suppressor Gene Promoter Methylation
Cancer Res., June 1, 2005; 65(11): 4673 - 4682.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
D. Lodygin, A. Epanchintsev, A. Menssen, J. Diebold, and H. Hermeking
Functional Epigenomics Identifies Genes Frequently Silenced in Prostate Cancer
Cancer Res., May 15, 2005; 65(10): 4218 - 4227.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
R. Schneider-Stock, M. Diab-Assef, A. Rohrbeck, C. Foltzer-Jourdainne, C. Boltze, R. Hartig, P. Schonfeld, A. Roessner, and H. Gali-Muhtasib
5-aza-Cytidine Is a Potent Inhibitor of DNA Methyltransferase 3a and Induces Apoptosis in HCT-116 Colon Cancer Cells via Gadd45- and p53-Dependent Mechanisms
J. Pharmacol. Exp. Ther., February 1, 2005; 312(2): 525 - 536.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
T. Yokochi and K. D. Robertson
Doxorubicin Inhibits DNMT1, Resulting in Conditional Apoptosis
Mol. Pharmacol., December 1, 2004; 66(6): 1415 - 1420.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
W.-G. Zhu, T. Hileman, Y. Ke, P. Wang, S. Lu, W. Duan, Z. Dai, T. Tong, M. A. Villalona-Calero, C. Plass, et al.
5-Aza-2'-deoxycytidine Activates the p53/p21Waf1/Cip1 Pathway to Inhibit Cell Proliferation
J. Biol. Chem., April 9, 2004; 279(15): 15161 - 15166.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
A. R. Karpf, A. W. Lasek, T. O. Ririe, A. N. Hanks, D. Grossman, and D. A. Jones
Limited Gene Activation in Tumor and Normal Epithelial Cells Treated with the DNA Methyltransferase Inhibitor 5-Aza-2'-deoxycytidine
Mol. Pharmacol., January 1, 2004; 65(1): 18 - 27.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
K. Liu, Y. F. Wang, C. Cantemir, and M. T. Muller
Endogenous Assays of DNA Methyltransferases: Evidence for Differential Activities of DNMT1, DNMT2, and DNMT3 in Mammalian Cells In Vivo
Mol. Cell. Biol., April 15, 2003; 23(8): 2709 - 2719.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
P. M. Campbell and M. Szyf
Human DNA methyltransferase gene DNMT1 is regulated by the APC pathway
Carcinogenesis, January 1, 2003; 24(1): 17 - 24.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
D. Machover, J. Zittoun, R. Saffroy, P. Broet, S. Giraudier, T. Magnaldo, E. Goldschmidt, B. Debuire, M. Orrico, Y. Tan, et al.
Treatment of Cancer Cells with Methioninase Produces DNA Hypomethylation and Increases DNA Synthesis
Cancer Res., August 15, 2002; 62(16): 4685 - 4689.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
J. E. Mullally and F. A. Fitzpatrick
Pharmacophore Model for Novel Inhibitors of Ubiquitin Isopeptidases That Induce p53-Independent Cell Death
Mol. Pharmacol., August 1, 2002; 62(2): 351 - 358.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
H. Shi, P. S. Yan, C.-M. Chen, F. Rahmatpanah, C. Lofton-Day, C. W. Caldwell, and T. H.-M. Huang
Expressed CpG Island Sequence Tag Microarray for Dual Screening of DNA Hypermethylation and Gene Silencing in Cancer Cells
Cancer Res., June 1, 2002; 62(11): 3214 - 3220.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
R. E. Watson and J. I. Goodman
Epigenetics and DNA Methylation Come of Age in Toxicology
Toxicol. Sci., May 1, 2002; 67(1): 11 - 16.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2001 by the American Society for Pharmacology and Experimental Therapeutics