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The von Hippel-Lindau protein sensitizes renal carcinoma cells to apoptotic stimuli through stabilization of BIM(EL).

Oncogene | Apr 23, 2009

von Hippel-Lindau (VHL) disease is caused by germ-line mutations in the VHL tumor suppressor gene and is the most common cause of inherited renal cell carcinoma (RCC). Mutations in the VHL gene also occur in a large majority of sporadic cases of clear-cell RCC, which have high intrinsic resistance to chemotherapy and radiotherapy. Here we show that VHL-deficient RCC cells express lower levels of the proapoptotic Bcl-2 family protein BIM(EL) and are more resistant to etoposide and UV radiation-induced death compared to the same cells stably expressing the wild-type VHL protein (pVHL). Reintroducing pVHL into VHL-null cells increased the half-life of BIM(EL) protein without affecting its mRNA expression, and overexpressing pVHL inhibited BIM(EL) polyubiquitination. Suppressing pVHL expression with RNA interference resulted in a decrease in BIM(EL) protein and a corresponding decrease in the sensitivity of RCC cells to apoptotic stimuli. Directly inhibiting BIM(EL) expression in pVHL-expressing RCC cells caused a similar decrease in cell death. These results demonstrate that pVHL acts to promote BIM(EL) protein stability in RCC cells, and that destabilization of BIM(EL) in the absence of pVHL contributes to the increased resistance of VHL-null RCC cells to certain apoptotic stimuli.

Pubmed ID: 19305426 RIS Download

Mesh terms: Apoptosis | Apoptosis Regulatory Proteins | Bcl-2-Like Protein 11 | Carcinoma, Renal Cell | Cell Line, Tumor | Extracellular Signal-Regulated MAP Kinases | Humans | Immunoprecipitation | Kidney Neoplasms | Membrane Proteins | Phosphorylation | Proto-Oncogene Proteins | Ubiquitin | Von Hippel-Lindau Tumor Suppressor Protein

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Associated grants

  • Agency: NINDS NIH HHS, Id: NS034400
  • Agency: NINDS NIH HHS, Id: R56 NS034400
  • Agency: NINDS NIH HHS, Id: NS058868
  • Agency: NINDS NIH HHS, Id: R01 NS034400-13
  • Agency: NINDS NIH HHS, Id: R01 NS058868-01A2
  • Agency: NINDS NIH HHS, Id: R01 NS034400
  • Agency: NINDS NIH HHS, Id: R01 NS058868

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