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Myc regulates VEGF production in B cells by stimulating initiation of VEGF mRNA translation

Abstract

Deregulated c-myc gene expression is associated with many human and animal cancers. Myc overexpression promotes the growth of blood and lymphatic vessels, which is due in part to induction of growth factors including vascular endothelial growth factor (VEGF). We determined that the P493-6 human B-cell line increases VEGF production 10-fold upon Myc overexpression. Myc overexpression in avian B cells similarly resulted in high level VEGF production. Real-time RT–PCR analyses showed that Myc did not alter the VEGF mRNA content of these cell lines, indicating that a post-transcriptional mechanism regulates VEGF production. VEGF mRNA translation was examined by RT–PCR analysis of monosome and polysome sucrose gradient fractions from Myc-on and Myc-off P493-6 cells. Myc increased VEGF mRNA translation initiation, as VEGF mRNA loading onto polysomes increased 14-fold in Myc-on cells, and the number of ribosomes loaded per VEGF mRNA increased threefold. This translational regulation is specific to VEGF mRNA, as total polysomes show the same sucrose gradient profile in Myc-on and Myc-off cells, with no change in the percent ribosomes in polysomes, or in the number of ribosomes per polysomal mRNA. Myc stimulates VEGF production by a rapamycin- and LY294002-sensitive pathway, which does not involve alteration of eIF4E activity.

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Acknowledgements

We thank Adam Geballe, Robert Eisenman, Carla Grandori, Stephanie Child, and Paul Neiman for their valuable expertise and advice, and Dirk Eick for providing P493-6 cells. This work was supported by a grant from the Elsa U Pardee Foundation and by Public Health Service Grant CA68328 from the National Cancer Institute.

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Correspondence to Alanna Ruddell.

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Supplementary information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Mezquita, P., Parghi, S., Brandvold, K. et al. Myc regulates VEGF production in B cells by stimulating initiation of VEGF mRNA translation. Oncogene 24, 889–901 (2005). https://doi.org/10.1038/sj.onc.1208251

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Keywords

  • Myc
  • VEGF
  • translational control
  • mammalian target of rapamycin
  • protein synthesis

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