Cytosolic Hsp60 Is Involved in the NF-κB-Dependent Survival of Cancer Cells via IKK RegulationReportar como inadecuado

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Cytoplasmic presence of Hsp60, which is principally a nuclear gene-encoded mitochondrial chaperonin, has frequently been stated, but its role in intracellular signaling is largely unknown. In this study, we demonstrate that the cytosolic Hsp60 promotes the TNF-α-mediated activation of the IKK-NF-κB survival pathway via direct interaction with IKKα-β in the cytoplasm. Selective loss or blockade of cytosolic Hsp60 by specific antisense oligonucleotide or neutralizing antibody diminished the IKK-NF-κB activation and the expression of NF-κB target genes, such as Bfl-1-A1 and MnSOD, which thus augmented intracellular ROS production and ASK1-dependent cell death, in response to TNF-α. Conversely, the ectopic expression of cytosol-targeted Hsp60 enhanced IKK-NF-κB activation. Mechanistically, the cytosolic Hsp60 enhanced IKK activation via upregulating the activation-dependent serine phosphorylation in a chaperone-independent manner. Furthermore, transgenic mouse study showed that the cytosolic Hsp60 suppressed hepatic cell death induced by diethylnitrosamine in vivo. The cytosolic Hsp60 is likely to be a regulatory component of IKK complex and it implicates the first mitochondrial factor that regulates cell survival via NF-κB pathway.

Autor: Jung Nyeo Chun, Boae Choi, Kyung Wha Lee, Doo Jae Lee, Dong Hoon Kang, Joo Young Lee, In Sung Song, Hye In Kim, Sang-Hee Lee, Hye



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