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그림 1. 방사선에 의해 노화되는 암세포에서 세포막의 콜레스테롤 수준 증가를 확인한 결과

그림 2. 방사선에 의해 활성화되는 두개의 다른 신호전달경로 즉, DNA 손상에 의한 세포사멸신호와 인테그린 활성화에 의한 세포생존신호의 발란스에 의해 암세포는 세포사멸과  세포노화의 두 다른 세포운명 사이에서 최종 세포의 운명을 선택하게 됨

Abstract
Cellular senescence refers to an irreversible growth arrest that is triggered by various intrinsic and extrinsic stresses. Many recent studies have demonstrated that cellular senescence plays a crucial role in the regression of tumors exposed to ionizing radiation (IR), but the underlying mechanism remains unknown. Here we show that the activation of integrin β4 is essential for IR-induced cellular senescence. IR treatment results in the phosphorylation of integrin β4 at tyrosine residue 1510, leading to activation of the integrin α6β4-Src-AKT signaling pathway. We further reveal that the IR-induced phosphorylation of integrin β4 is regulated by the cholesterol content and membrane fluidity. We also find that IR-induced p53-caspase signaling is independent of integrin α6β4-Src-AKT signaling. Finally, we show that siRNA- or inhibitor-mediated blockade of integrin α6β4-Src-AKT signaling switches the post-irradiation fate from senescence to apoptosis, under p53 activated condition, in both cancer cells and tumor tissues of xenograft mice. On the basis of our finding that, integrin α6β4 is specifically activated and acts primarily to induce premature senescence in irradiated cancer cells, we propose that this integrin may be a valuable target and biomarker for radiotherapy.

Author information

Jung SH1,2, Lee M3, Park HA1,2, Lee HC1,2, Kang D1,2, Hwang HJ1,2, Park C2, Yu DM4, Jung YR3, Hong MN3, Kim YN5, Park HJ2,6, Ko YG4, Lee JS7,8.
1
Department of Molecular Medicine, Inha University College of Medicine, Incheon, Korea.
2
Hypoxia-related Disease Research Center, Inha University College of Medicine, Incheon, Korea.
3
Radiation Non-clinical Center, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
4
Division of Life Sciences, Korea University, Seoul, Korea.
5
Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Korea.
6
Department of Microbiology, Inha University College of Medicine, Incheon, Korea.
7
Department of Molecular Medicine, Inha University College of Medicine, Incheon, Korea. jaeslee@inha.ac.kr.
8
Hypoxia-related Disease Research Center, Inha University College of Medicine, Incheon, Korea. jaeslee@inha.ac.kr.

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