title: Cytosolic Hsp60 is involved in the NF-kappaB-dependent survival of cancer cells via IKK regulation.
abstract: 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-alpha-mediated activation of the IKK/NF-kappaB survival pathway via direct interaction with IKKalpha/beta in the cytoplasm. Selective loss or blockade of cytosolic Hsp60 by specific antisense oligonucleotide or neutralizing antibody diminished the IKK/NF-kappaB activation and the expression of NF-kappaB target genes, such as Bfl-1/A1 and MnSOD, which thus augmented intracellular ROS production and ASK1-dependent cell death, in response to TNF-alpha. Conversely, the ectopic expression of cytosol-targeted Hsp60 enhanced IKK/NF-kappaB 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-kappaB pathway.
authors.affiliation: Division of Life and Pharmaceutical Science and Center for Cell Signaling and Drug Discovery Research, Ewha Womans University, Seoul, Korea.
authors.forename: Jung Nyeo
authors.initials: JN
authors.lastname: Chun
authors.forename: Boae
authors.initials: B
authors.lastname: Choi
authors.forename: Kyung Wha
authors.initials: KW
authors.lastname: Lee
authors.forename: Doo Jae
authors.initials: DJ
authors.lastname: Lee
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Kang
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Lee
authors.forename: In Sung
authors.initials: IS
authors.lastname: Song
authors.forename: Hye In
authors.initials: HI
authors.lastname: Kim
authors.forename: Sang-Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Hyeon Soo
authors.initials: HS
authors.lastname: Kim
authors.forename: Na Kyung
authors.initials: NK
authors.lastname: Lee
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Kong-Joo
authors.initials: KJ
authors.lastname: Lee
authors.forename: Jaesang
authors.initials: J
authors.lastname: Kim
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Kang
mesh_terms: D000818:Animals; D002470:Cell Survival; D018834:Chaperonin 60 / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000473:pathology*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018834:Chaperonin 60; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D014409:Tumor Necrosis Factor-alpha; D013482:Superoxide Dismutase; D051550:I-kappa B Kinase