title: Cancer cells promote survival through depletion of the von Hippel-Lindau tumor suppressor by protein crosslinking.
abstract: Nuclear factor-κB (NF-κB) and insulin-like growth factor-1 (IGF-1)-mediated signaling is associated with different tumors including renal cell carcinoma. NF-κB- and IGF-1-mediated signaling is found to be inhibited in the presence of wild-type von Hippel-Lindau (VHL) tumor suppresser gene. Therefore, negative regulator of VHL may be a good target for regulating NF-κB and IGF-1R. In this study, we found that VHL, a tumor suppressor protein that downregulates the NF-κB activity and the stability of IGF-1R was depleted by TGase 2 through polymerization via crosslinking and proteasomal degradation in kidney, breast and ovary cancer cell lines. We also found that TGase 2 knockdown promotes hypoxia-inducible factor 1α (HIF-1α) degradation, and thereby decrease HIF-1α transcriptional activity. Importantly, VHL expression was decreased in vivo in TGase-2-transgenic mice, and this was associated with increased NF-κB activity and the levels of expression of IGF-1R, HIF-1α and erythropoietin in kidney tissue. These results suggest a novel mechanism of regulation of the VHL tumor suppressor by TGase 2 that appears to be independent of the known cancer regulatory mechanisms.
authors.affiliation: Cancer Cell and Molecular Biology Branch, Division of Cancer Biology, Research Institute, Goyang, Korea.
authors.forename: D-S
authors.initials: DS
authors.lastname: Kim
authors.forename: Y-B
authors.initials: YB
authors.lastname: Choi
authors.forename: B-G
authors.initials: BG
authors.lastname: Han
authors.forename: S-Y
authors.initials: SY
authors.lastname: Park
authors.forename: Y
authors.initials: Y
authors.lastname: Jeon
authors.forename: D-H
authors.initials: DH
authors.lastname: Kim
authors.forename: E-R
authors.initials: ER
authors.lastname: Ahn
authors.forename: J-E
authors.initials: JE
authors.lastname: Shin
authors.forename: B I
authors.initials: BI
authors.lastname: Lee
authors.forename: H
authors.initials: H
authors.lastname: Lee
authors.forename: K-M
authors.initials: KM
authors.lastname: Hong
authors.forename: S-Y
authors.initials: SY
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D015536:Down-Regulation; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors; D016147:Genes, Tumor Suppressor; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000037:antagonists & inhibitors; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D007334:Insulin-Like Growth Factor I; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D019204:GTP-Binding Proteins