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PF-4708671, a specific inhibitor of p70 ribosomal S6 kinase 1, activates Nrf2 by promoting p62-dependent autophagic degradation of Keap1

Authors
 Jeong Su Park ; Dong Hoon Kang ; Soo Han Bae ; Da Hyun Lee 
Citation
 Biochemical and Biophysical Research Communications, Vol.466(3) : 499~504, 2015 
Journal Title
 Biochemical and Biophysical Research Communications 
ISSN
 0006-291X 
Issue Date
2015
Abstract
p70 ribosomal S6 kinase 1 (S6K1) is an important serine/threonine kinase and downstream target of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway. PF-4708671 is a specific inhibitor of S6K1, and prevents S6K1-mediated phosphorylation of the S6 protein. PF-4708671 treatment often leads to apoptotic cell death. However, the protective mechanism against PF-4708671-induced cell death has not been elucidated. The nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway is essential for protecting cells against oxidative stress. p62, an adaptor protein in the autophagic process, enhances Nrf2 activation through the impairment of Keap1 activity. In this study, we showed that PF-4708671 induces autophagic Keap1 degradation-mediated Nrf2 activation in p62-dependent manner. Furthermore, p62-dependent Nrf2 activation plays a crucial role in protecting cells from PF-4708671-mediated apoptosis.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/141280
DOI
10.1016/j.bbrc.2015.09.059
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Dept. of Life Science
Yonsei Authors
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Link
 http://www.sciencedirect.com/science/article/pii/S0006291X15305787
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