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Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity

Oncogene volume 18, pages 1529–1535 (1999)Cite this article

Abstract

The VHL tumor suppressor gene has previously been reported to encode a protein of 213 amino acid residues. Here we report the identification of a second major VHL gene product with an apparent molecular weight of 18 kD, pVHL18, which appears to arise from alternate translation initiation at a second AUG codon (codon 54) within the VHL open reading frame. In vitro and in vivo studies indicate that the internal codon in the VHL mRNA is necessary and sufficient for production of pVHL18. pVHL18 can bind to elongin B, elongin C, and Hs-CUL2. When reintroduced into renal carcinoma cells that lack a wild-type VHL allele, pVHL18 suppresses basal levels of VEGF expression, restores hypoxia-inducibility of VEGF expression, and inhibits tumor formation in nude mice. These data strongly support the existence of two distinct VHL gene products in VHL tumor suppression.

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Acknowledgements

We would like to acknowledge Dr William S Lane of the Harvard Microchemistry Facility for his assistance in peptide sequencing. In addition we acknowledge Dr Frank Lee for his help with the tumor suppression experiments in vivo, and Tim Skinner for expert technical assistance.

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Authors and Affiliations

  1. Department of Functional Genomics, Genome Therapeutics Corporation, 100 Beaver Street, Waltham, 02154, Massachusetts, USA

    Catherine Blankenship, Bernd Seizinger & Nikolai Kley

  2. Department of Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, 08540, New Jersey, USA

    Joseph G Naglich

  3. Department of Metabolic Diseases, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, 08540, New Jersey, USA

    Jean M Whaley

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  1. Catherine Blankenship
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  2. Joseph G Naglich
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  4. Bernd Seizinger
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  5. Nikolai Kley
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Blankenship, C., Naglich, J., Whaley, J. et al. Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity. Oncogene 18, 1529–1535 (1999). https://doi.org/10.1038/sj.onc.1202473

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