Abstract
Nuclear factor-B (NF-B) 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-B 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.
Original language | English (US) |
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Pages (from-to) | 4780-4790 |
Number of pages | 11 |
Journal | Oncogene |
Volume | 30 |
Issue number | 48 |
DOIs | |
State | Published - Dec 1 2011 |
Externally published | Yes |
Keywords
- EPO
- HIF-1α
- IGF-1R
- NF-κB
- Transglutaminase 2
- Von Hippel-Lindau
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research