title: IGF-I enhances cellular senescence via the reactive oxygen species-p53 pathway.
abstract: Cellular senescence is characterized by growth arrest, enlarged and flattened cell morphology, the expression of senescence-associated β-galactosidase (SA-β-gal), and by activation of tumor suppressor networks. Insulin-like growth factor-I (IGF-I) plays a critical role in cellular growth, proliferation, tumorigenesis, and regulation of aging. In the present study, we show that IGF-I enhances cellular senescence in mouse, rat, and human primary cells in the confluent state. IGF-I induced expression of a DNA damage marker, γH2AX, the increased levels of p53 and p21 proteins, and activated SA-β-gal. In the confluent state, an altered downstream signaling of IGF-I receptor was observed. Treatment with a reactive oxygen species (ROS) scavenger, N-acetylcystein (NAC) significantly suppressed induction of these markers, indicating that ROS are involved in the induction of cellular senescence by IGF-I. In p53-null mouse embryonic fibroblasts, the IGF-I-induced augmentation of SA-β-gal and p21 was inhibited, demonstrating that p53 is required for cellular senescence induced by IGF-I. Thus, these data reveal a novel pathway whereby IGF-I enhances cellular senescence in the ROS and p53-dependent manner and may explain the underlying mechanisms of IGF-I involvement in tumorigenesis and in regulation of aging.
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Anastasia-Evi
authors.initials: AE
authors.lastname: Handayaningsih
authors.forename: Michiko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Hidenori
authors.initials: H
authors.lastname: Fukuoka
authors.forename: Genzo
authors.initials: G
authors.lastname: Iguchi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nishizawa
authors.forename: Masaaki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Kentaro
authors.initials: K
authors.lastname: Suda
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D007334:Insulin-Like Growth Factor I