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Role of apoptosis repressor with caspase recruitment domain (ARC) in cellular senescence of human diploid fibroblast

Authors
Lee, Yun-Yeong; Lim, In Kyoung
Department
Department of Biochemistry & Molecular Biology
Abstract
Cellular senescence plays a key role in the biology of aging and carcinogenesis. Hayflick and Moorhead earlier described the replicative senescence revealing a limited proliferative capacity, and postulated cellular senescence as an in vitro manifestation of human aging. Apoptosis repressor with caspase recruitment domain (ARC) has been known as a highly potent and multifunctional inhibitor of apoptosis that is physiologically expressed mainly n the post-mitotic cells such as cardiomyocytes, skeletal muscle cells and neurons. It is also found to be upregulated in various forms of malignant tumors, and impairs the cellular apoptotic responsiveness to a wide range of stresses and insults, including extrinsic apoptosis initiation via death receptor ligands, dysregulation of cellular Ca2+ homeostasis and endoplasmatic reticulum (ER) stress,genotoxic drugs, ionizing radiation, oxidative stress and hypoxia. ARC is subject to both transcriptional and post-translational regulation and exhibits its function through a multitude of molecular interactions with upstream transducers of apoptosis signals. In the present work, we have observed that ARC expression was upregulated in senescent HDF compared with that of young cells. Based on the reports that senescent cells are more resistant to environmental stress than young or mid-old cells, we hypothesized that ARC may be an important factor contributing toward stress resistance and survival of senescent cells. By employing lentiviral infection to maintain constitutive knockdown or overexpression, therefore, we assessed the role of ARC in cellular senescence of HDF cells. studies regarding various phenotypes of replicative- or stress-induced senescence and underlined molecular mechanisms will be discussed.
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