We have found previously that ascorbic acid (vitamin C), as well as acting as a radical scavenger, may modulate the expression of several genes [i.e. fra-1, glutathione S-transferase Pi (GSTpi) and Mut L homologue-1 (MLH1)] in human keratinocytes. In the present paper, we demonstrate that MLH1, as well as its downstream target p73, can be positively modulated by this antioxidant vitamin, indeed, up-regulation of the two mRNAs was observed after just 2h, and increased further up to 16h of treatment. Modulation of MLH1 and p73 gene expression improves cellular susceptibility to apoptosis triggered by the DNA-damaging agent cisplatin. Indeed, in ascorbate-supplemented cells, increased cisplatin-induced apoptosis was seen, involving activation of the MLH1/c-Abl/p73 signalling cascade. Our results were further confirmed by studies performed on genetically defined mutants, i.e. mouse embryo fibroblasts derived from knock-out animals for c-Abl or p53, as well as human colon carcinoma cell lines deficient in MLH1. The increased sensitivity to cisplatin observed in ascorbate-loaded cells appeared to be dependent exclusively on MLH1 and c-Abl expression, and independent of p53. These data suggest a potential mechanism accounting for the anti-carcinogenic and anti-cancer activities of vitamin C.
Skip Nav Destination
Article navigation
June 2002
- PDF Icon PDF LinkFront Matter
Research Article|
June 01 2002
Ascorbate up-regulates MLH1 (Mut L homologue-1) and p73: implications for the cellular response to DNA damage
M. Valeria CATANI;
M. Valeria CATANI
∗Biochemistry Laboratory, IDI-IRCCS, c/o Department of Experimental Medicine & Biochemical Sciences, University of Rome Tor Vergata, Via Tor Vergata 135, 00133 Rome, Italy
Search for other works by this author on:
Antonio COSTANZO;
Antonio COSTANZO
†Laboratory of Gene Expression, Fondazione A. Cesalpino, University of Rome La Sapienza, 00161 Rome, Italy
Search for other works by this author on:
Isabella SAVINI;
Isabella SAVINI
‡Department of Experimental Medicine & Biochemical Sciences, University of Rome Tor Vergata, Via Tor Vergata 135, 00133 Rome, Italy
Search for other works by this author on:
Massimo LEVRERO;
Massimo LEVRERO
†Laboratory of Gene Expression, Fondazione A. Cesalpino, University of Rome La Sapienza, 00161 Rome, Italy
Search for other works by this author on:
Vincenzo DE LAURENZI;
Vincenzo DE LAURENZI
‡Department of Experimental Medicine & Biochemical Sciences, University of Rome Tor Vergata, Via Tor Vergata 135, 00133 Rome, Italy
Search for other works by this author on:
Jean Y.J. WANG;
Jean Y.J. WANG
§Department of Biology and the Cancer Center, University of California, La Jolla, CA 92093-90322, U.S.A.
Search for other works by this author on:
Gerry MELINO;
Gerry MELINO
‡Department of Experimental Medicine & Biochemical Sciences, University of Rome Tor Vergata, Via Tor Vergata 135, 00133 Rome, Italy
Search for other works by this author on:
Luciana AVIGLIANO
Luciana AVIGLIANO
1
‡Department of Experimental Medicine & Biochemical Sciences, University of Rome Tor Vergata, Via Tor Vergata 135, 00133 Rome, Italy
1To whom correspondence should be addressed (e-mail avigliano@uniroma2.it).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
November 22 2001
Revision Received:
January 30 2002
Accepted:
March 22 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 364 (2): 441–447.
Article history
Received:
November 22 2001
Revision Received:
January 30 2002
Accepted:
March 22 2002
Citation
M. Valeria CATANI, Antonio COSTANZO, Isabella SAVINI, Massimo LEVRERO, Vincenzo DE LAURENZI, Jean Y.J. WANG, Gerry MELINO, Luciana AVIGLIANO; Ascorbate up-regulates MLH1 (Mut L homologue-1) and p73: implications for the cellular response to DNA damage. Biochem J 1 June 2002; 364 (2): 441–447. doi: https://doi.org/10.1042/bj20011713
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Captcha Validation Error. Please try again.