title: Melatonin triggers p53Ser phosphorylation and prevents DNA damage accumulation.
abstract: Several epidemiological studies have shown that high levels of melatonin, an indolic hormone secreted mainly by the pineal gland, reduce the risks of developing cancer, thus suggesting that melatonin triggers the activation of tumor-suppressor pathways that lead to the prevention of malignant transformation. This paper illustrates that melatonin induces phosphorylation of p53 at Ser-15 inhibiting cell proliferation and preventing DNA damage accumulation of both normal and transformed cells. This activity requires p53 and promyelocytic leukemia (PML) expression and efficient phosphorylation of p53 at Ser-15 residue. Melatonin-induced p53 phosphorylation at Ser-15 residue does not require ataxia telangiectasia-mutated activity, whereas it is severely impaired upon chemical inhibition of p38 mitogen-activated protein kinase activity. By and large, these findings imply that the activation of the p53 tumor-suppressor pathway is a critical mediator of melatonin and its anticancer effects. Therefore, it provides molecular insights into increasing observational evidence for the role that melatonin has in cancer prevention.
authors: Molecular Chemoprevention Group, Molecular Medicine Department, Italian National Cancer Institute Regina Elena, Rome, Italy. strano@ifo.it
authors: R
authors: R
authors: Santoro
authors: M
authors: M
authors: Marani
authors: G
authors: G
authors: Blandino
authors: P
authors: P
authors: Muti
authors: S
authors: S
authors: Strano
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D000071156:Promyelocytic Leukemia Protein; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012694:Serine / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000975:Antioxidants; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D011725:Pyridines; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D012694:Serine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D008550:Melatonin; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one