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Protein kinase CK2 activates Nrf2 via autophagic degradation of Keap1 and activation of AMPK in human cancer cells
Da eun Jang1,# (Graduate student), Junbin Song1,# (Graduate student), Jeong-Woo Park 1 (Graduate student), Soo-Hyun Yoon2 (Research worker), Young-Seuk Bae 1,* (Professor)
1School of Life Sciences, BK21 Plus KNU Creative BioResearch Group and 2Research Institute of Pharmaceutical Sciences, Kyungpook National University
Abstract
Protein kinase CK2 downregulation induces premature senescence in various human cell types via activation of the reactive oxygen species (ROS)–p53–p21 Cip1/WAF1 pathway. The transcription factor “nuclear factor erythroid 2-related factor 2” (Nrf2) plays an important role in maintaining intracellular redox homeostasis. In this study, Nrf2 overexpression attenuated CK2 downregulation–induced ROS production and senescence markers including SA-モ-gal staining and activation of p53–p21Cip1/WAF1 in human breast (MCF-7) and colon (HCT116) cancer cells. CK2 downregulation reduced the transcription of Nrf2 target genes, such as glutathione S-transferase, glutathione peroxidase 2, and glutathione reductase 1. Furthermore, CK2 downregulation destabilized Nrf2 protein via inhibiting autophagic degradation of Kelch-like ECH-associated protein 1 (Keap1). Finally, CK2 downregulation decreased the nuclear import of Nrf2 by deactivating AMP-activated protein kinase (AMPK). Collectively, our data suggest that both Keap1 stabilization and AMPK inactivation are associated with decreased activity of Nrf2 in CK2 downregulation–induced cellular senescence.
Abstract, Accepted Manuscript(in press) [Submitted on February 25, 2020, Accepted on March 31, 2020]
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