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

D. S. Kim, Y. B. Choi, B. G. Han, S. Y. Park, Y. Jeon, D. H. Kim, E. R. Ahn, J. E. Shin, B. I. Lee, H. Lee, K. M. Hong, S. Y. Kim

Research output: Contribution to journalArticle

19 Scopus citations

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 languageEnglish (US)
Pages (from-to)4780-4790
Number of pages11
JournalOncogene
Volume30
Issue number48
DOIs
StatePublished - Dec 1 2011
Externally publishedYes

Keywords

  • EPO
  • HIF-1α
  • IGF-1R
  • NF-κB
  • Transglutaminase 2
  • Von Hippel-Lindau

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Kim, D. S., Choi, Y. B., Han, B. G., Park, S. Y., Jeon, Y., Kim, D. H., Ahn, E. R., Shin, J. E., Lee, B. I., Lee, H., Hong, K. M., & Kim, S. Y. (2011). Cancer cells promote survival through depletion of the von Hippel-Lindau tumor suppressor by protein crosslinking. Oncogene, 30(48), 4780-4790. https://doi.org/10.1038/onc.2011.183