| First Author | Kim DS | Year | 2011 |
| Journal | Oncogene | Volume | 30 |
| Issue | 48 | Pages | 4780-90 |
| PubMed ID | 21625219 | Mgi Jnum | J:178571 |
| Mgi Id | MGI:5299289 | Doi | 10.1038/onc.2011.183 |
| Citation | Kim DS, et al. (2011) Cancer cells promote survival through depletion of the von Hippel-Lindau tumor suppressor by protein crosslinking. Oncogene 30(48):4780-90 |
| abstractText | Nuclear factor-kappaB (NF-kappaB) and insulin-like growth factor-1 (IGF-1)-mediated signaling is associated with different tumors including renal cell carcinoma. NF-kappaB- 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-kappaB and IGF-1R. In this study, we found that VHL, a tumor suppressor protein that downregulates the NF-kappaB 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 1alpha (HIF-1alpha) degradation, and thereby decrease HIF-1alpha transcriptional activity. Importantly, VHL expression was decreased in vivo in TGase-2-transgenic mice, and this was associated with increased NF-kappaB activity and the levels of expression of IGF-1R, HIF-1alpha 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. |
