p53-dependent pathway of radio-induced apoptosis is altered in Fanconi anemia.
Fanconi anemia belongs to a group of human genetic diseases characterized by chromosomal instability, sensitivity to genotoxic agents associated to impaired processing of DNA lesions, cell cycle anomalies and cancer predisposition. We recently added to this list of distinctive features reduced production of interleukin 6 and overproduction of tumor necrosis factor alpha. Since growth factor deprivation, TNF alpha treatment or DNA damage can trigger apoptosis, we monitored the apoptotic response of FA cell lines. We show here that, although the spontaneous rate of apoptosis is slightly more elevated in FA than in normal cell cultures, the apoptosis induced by gamma-irradiation is drastically reduced in FA. Since the induction of apoptosis by radiation is a p53-dependent mechanism, the induction of this protein in FA cells was also examined. We found that the p53 protein is not radio-induced in FA cells belonging to the two genetic complementation groups examined (C and D), in contrast to normal cells. Moreover, the same impairment in p53 induction is observed after exposure to mitomycin C, a chemical agent for which FA cells demonstrate a specific cellular and chromosomal hypersensitivity, as well as after u.v.-B irradiation, an agent known to cause oxidative stress. These observations are in line with recent reports showing that at least certain cell lines from other chromosome breakage syndromes, such as ataxia telangiectasia and Bloom syndrome, may be also defective for radiation-induced increase of p53 protein. As the p53 tumor suppressor gene encodes a transcriptional activator whose targets include genes that regulate genomic stability, cellular response to DNA damage and cell cycle progression, we suggest that altered expression of p53 may be relevant to the FA phenotype.
Rosselli
F
F
URA 1292 du CNRS, Institut Curie-Biologie, Paris, France.
Ridet
A
A
Soussi
T
T
Duchaud
E
E
Alapetite
C
C
Moustacchi
E
E
D002453:Cell Cycle; D002478:Cells, Cultured; D005199:Fanconi Anemia / Q000235:genetics / Q000473:pathology*; D016158:Genes, p53; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D010641:Phenotype