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., C.A. (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.
|Tipologia:||Articolo su rivista|
|Citazione:||Catani M.V., C.A. (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.|
|IF:||Con Impact Factor ISI|
|Settore Scientifico Disciplinare:||Settore MED/35 - Malattie Cutanee e Veneree|
|Revisione (peer review):||Sì, ma tipo non specificato|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1042/BJ20011713|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||2002|
|Titolo:||Ascorbate up-regulates MLH1 (Mut L homologue-1) and p73: Implications for the cellular response to DNA damage|
|Autori:||Catani M.V., Costanzo A., Savini I., Levrero M., De Laurenzi V., Wang J.Y.J., Melino G., Avigliano L.|
|Appare nelle tipologie:||01 - Articolo su rivista|