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Cancer cells promote survival through depletion of the von Hippel-Lindau tumor suppressor by protein crosslinking.
- Source :
-
Oncogene [Oncogene] 2011 Dec 01; Vol. 30 (48), pp. 4780-90. Date of Electronic Publication: 2011 May 30. - Publication Year :
- 2011
-
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.
- Subjects :
- Amino Acid Sequence
Animals
Cell Line, Tumor
Down-Regulation
GTP-Binding Proteins antagonists & inhibitors
Genes, Tumor Suppressor
Humans
Insulin-Like Growth Factor I metabolism
Mice
Mice, Transgenic
Molecular Sequence Data
NF-kappa B metabolism
Neoplasms metabolism
Protein Glutamine gamma Glutamyltransferase 2
Transglutaminases antagonists & inhibitors
Von Hippel-Lindau Tumor Suppressor Protein chemistry
Von Hippel-Lindau Tumor Suppressor Protein genetics
Cell Survival
Neoplasms pathology
Von Hippel-Lindau Tumor Suppressor Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 30
- Issue :
- 48
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 21625219
- Full Text :
- https://doi.org/10.1038/onc.2011.183