期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 425, 期 2, 页码 478-484出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2012.07.140
关键词
IGF-I; Cellular senescence; ROS; p53; Longevity
资金
- Japanese Ministry of Education, Culture, Sports, Science, and Technology [19591077, 70301281]
- Ministry of Health, Labor, and Welfare, Japan
- Grants-in-Aid for Scientific Research [19591077] Funding Source: KAKEN
Cellular senescence is characterized by growth arrest, enlarged and flattened cell morphology, the expression of senescence-associated beta-galactosidase (SA-beta-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, gamma H2AX, the increased levels of p53 and p21 proteins, and activated SA-beta-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-beta-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. (c) 2012 Elsevier Inc. All rights reserved.
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