title: The p53-dependent expression of frataxin controls 5-aminolevulinic acid-induced accumulation of protoporphyrin IX and photo-damage in cancerous cells.
abstract: Mitochondrial frataxin is involved in various functions such as iron homeostasis, iron-sulfur cluster biogenesis, the protection from oxidative stress and apoptosis and acts as a tumor suppressor protein. We now show that the expression of frataxin is stimulated in a p53-dependent manner and prove that frataxin is a direct p53 target gene by showing that the p53-responsive element in the promoter of the mouse frataxin gene is bound by p53. The bacterial expression of human frataxin stimulated maturation of human ferrochelatase, which catalyzes the insertion of iron into protoporphyrin at the last step of heme biosynthesis. Overexpression of frataxin in human cancer A431 and HeLa cells lowered 5-aminolevulinic acid(ALA)-induced accumulation of protoporphyrin and induced resistance to ALA-induced photo-damage, whereas p53 silencing with siRNA in non tumor HEK293T cells down-regulated the expression of frataxin and increased the accumulation of protoporphyrin. Thus, the decrease of the expression of frataxin unregulated by p53 in tumor cells enhances ALA-induced photo-damage, by down-regulation of mitochondrial functions.
authors.affiliation: Department of Biotechnology, Kyoto Institute of Technology, Kyoto, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Sawamoto
authors.forename: Takafumi
authors.initials: T
authors.lastname: Imai
authors.forename: Mana
authors.initials: M
authors.lastname: Umeda
authors.forename: Koji
authors.initials: K
authors.lastname: Fukuda
authors.forename: Takao
authors.initials: T
authors.lastname: Kataoka
authors.forename: Shigeru
authors.initials: S
authors.lastname: Taketani
mesh_terms: D000622:Aminolevulinic Acid / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D005294:Ferrochelatase / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007501:Iron / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011524:Protoporphyrins / Q000096:biosynthesis*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000096923:Frataxin
chemical_list: D000622:Aminolevulinic Acid; D005294:Ferrochelatase; D007501:Iron; D033862:Iron-Binding Proteins; D011524:Protoporphyrins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D000096923:Frataxin; C028025:protoporphyrin IX