Carcinogenesis Advance Access originally published online on July 17, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Carcinogenesis, Vol. 24, No. 10, 1601-1614,
October 2003
© 2003 Oxford University Press
CANCER BIOLOGY |
The effect of potent iron chelators on the regulation of p53: examination of the expression, localization and DNA-binding activity of p53 and the transactivation of WAF1
Children's Cancer Institute Australia for Medical Research, Iron Metabolism and Chelation Program, PO Box 81, High Street, Randwick, Sydney, New South Wales 2031, Australia and The Heart Research Institute, Iron Metabolism and Chelation Group, 145 Missenden Road, Camperdown, Sydney, New South Wales 2050, Australia
Iron (Fe) chelators induce a G1/S arrest and several of these are undergoing clinical trials as anticancer agents. Despite this, little is known concerning the precise function of Fe in cell cycle progression and the role of p53 in this process. The aim of this study was to assess the effect of Fe chelators on p53 and the mechanism involved in the chelator-mediated increase in mRNA levels of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1. Cells were incubated with the potent Fe chelator 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) and the results compared with those from cells treated with actinomycin D (Act D), which induces p53. Following incubation with 311, a 3- to 5-fold increase in nuclear p53 protein was observed in cells with wild-type p53. In addition, 311 increased p53 DNA-binding activity 2-fold, while Act D increased it 3- to 5-fold in cells with native p53. To determine the role of p53 in WAF1 transcription, a reporter construct was used consisting of a WAF1 promoter containing the p53-binding site. In cells with wild-type p53, chelators had no effect on luciferase activity, while the positive control, Act D, caused a significant increase. Hence, despite increased p53 protein expression and p53 DNA-binding activity following chelation, these latter results suggested it had no role in up-regulating WAF1 mRNA. Our experiments demonstrated: (i) that the elevated WAF1 mRNA expression after Fe chelation was due to increased transcription and also to a post-transcriptional mechanism that was sensitive to cycloheximide; and (ii) that Fe-chelation increased WAF1 expression through a p53-independent pathway.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. J. Assinder, Q. Dong, H. Mangs, and D. R. Richardson Pharmacological Targeting of the Integrated Protein Kinase B, Phosphatase and Tensin Homolog Deleted on Chromosome 10, and Transforming Growth Factor-{beta} Pathways in Prostate Cancer Mol. Pharmacol., March 1, 2009; 75(3): 429 - 436. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Klekota and F. P. Roth Chemical substructures that enrich for biological activity Bioinformatics, November 1, 2008; 24(21): 2518 - 2525. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Fu and D. R. Richardson Iron chelation and regulation of the cell cycle: 2 mechanisms of posttranscriptional regulation of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1 by iron depletion Blood, July 15, 2007; 110(2): 752 - 761. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Nurtjahja-Tjendraputra, D. Fu, J. M. Phang, and D. R. Richardson Iron chelation regulates cyclin D1 expression via the proteasome: a link to iron deficiency-mediated growth suppression Blood, May 1, 2007; 109(9): 4045 - 4054. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Kovacevic and D. R. Richardson The metastasis suppressor, Ndrg-1: a new ally in the fight against cancer Carcinogenesis, December 1, 2006; 27(12): 2355 - 2366. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Sanchez, B. Galy, T. Dandekar, P. Bengert, Y. Vainshtein, J. Stolte, M. U. Muckenthaler, and M. W. Hentze Iron Regulation and the Cell Cycle: IDENTIFICATION OF AN IRON-RESPONSIVE ELEMENT IN THE 3'-UNTRANSLATED REGION OF HUMAN CELL DIVISION CYCLE 14A mRNA BY A REFINED MICROARRAY-BASED SCREENING STRATEGY J. Biol. Chem., August 11, 2006; 281(32): 22865 - 22874. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. S. Andersen, L. Gambling, G. Holtrop, and H. J. McArdle Maternal Iron Deficiency Identifies Critical Windows for Growth and Cardiovascular Development in the Rat Postimplantation Embryo J. Nutr., May 1, 2006; 136(5): 1171 - 1177. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. S. Kalinowski and D. R. Richardson The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer Pharmacol. Rev., December 1, 2005; 57(4): 547 - 583. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Y. Yeung, K. P. Lai, H. Y. Chan, N. K. Mak, G. F. Wagner, and C. K. C. Wong Hypoxia-Inducible Factor-1-Mediated Activation of Stanniocalcin-1 in Human Cancer Cells Endocrinology, November 1, 2005; 146(11): 4951 - 4960. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. T.V. Le and D. R. Richardson Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation Blood, November 1, 2004; 104(9): 2967 - 2975. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Yuan, D. B. Lovejoy, and D. R. Richardson Novel di-2-pyridyl-derived iron chelators with marked and selective antitumor activity: in vitro and in vivo assessment Blood, September 1, 2004; 104(5): 1450 - 1458. [Abstract] [Full Text] [PDF]
|
|