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 2 In, and increased further up to 16 h 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.

Catani, M.v., Costanzo, A., Savini, I., Levrero, M., De Laurenzi, V., Wang, J., et al. (2002). Ascorbate up-regulates MLH1 (Mut L homologue-1) and p73: Implications for the cellular response to DNA damage. BIOCHEMICAL JOURNAL, 364(2), 441-447 [10.1042/BJ20011713].

Ascorbate up-regulates MLH1 (Mut L homologue-1) and p73: Implications for the cellular response to DNA damage

CATANI, MARIA VALERIA;COSTANZO, ANTONIO;SAVINI, ISABELLA;MELINO, GENNARO;AVIGLIANO, LUCIANA
2002-01-01

Abstract

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 2 In, and increased further up to 16 h 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.
2002
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/35 - MALATTIE CUTANEE E VENEREE
English
Con Impact Factor ISI
c-Abl; Cell death; Cisplatin; Vitamin C
Catani, M.v., Costanzo, A., Savini, I., Levrero, M., De Laurenzi, V., Wang, J., et al. (2002). Ascorbate up-regulates MLH1 (Mut L homologue-1) and p73: Implications for the cellular response to DNA damage. BIOCHEMICAL JOURNAL, 364(2), 441-447 [10.1042/BJ20011713].
Catani, Mv; Costanzo, A; Savini, I; Levrero, M; De Laurenzi, V; Wang, Jyj; Melino, G; Avigliano, L
Articolo su rivista
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/52573
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