Cancer cells promote survival through depletion of the von Hippel-Lindau tumor suppressor by protein crosslinking.

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.
Mesh Terms:
Amino Acid Sequence, Animals, Cell Line, Tumor, Cell Survival, Down-Regulation, GTP-Binding Proteins, Genes, Tumor Suppressor, Humans, Insulin-Like Growth Factor I, Mice, Mice, Transgenic, Molecular Sequence Data, NF-kappa B, Neoplasms, Transglutaminases, Von Hippel-Lindau Tumor Suppressor Protein
Oncogene
Date: Dec. 01, 2011
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