The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
Hypoxia Inducible Factor Activates the Transforming Growth Factor-α/Epidermal Growth Factor Receptor Growth Stimulatory Pathway in VHL-/- Renal Cell Carcinoma Cells
Open accessAbstract
Bi-allelic-inactivating mutations of the VHL tumor suppressor gene are found in the majority of clear cell renal cell carcinomas (VHL(-/-) RCC). VHL(-/-) RCC cells overproduce hypoxia-inducible genes as a consequence of constitutive, oxygen-independent activation of hypoxia inducible factor (HIF). While HIF activation explains the highly vascularized nature of VHL loss lesions, the relative role of HIF in oncogenesis and loss of growth control remains unknown. Here, we report that HIF plays a central role in promoting unregulated growth of VHL(-/-) RCC cells by activating the transforming growth factor-alpha (TGF-alpha)/epidermal growth factor receptor (EGF-R) pathway. Dominant-negative HIF and enzymatic inhibition of EGF-R were equally efficient at abolishing EGF-R activation and serum-independent growth of VHL(-/-) RCC cells. TGF-alpha is the only known EGF-R ligand that has a VHL-dependent expression profile and its overexpression by VHL(-/-) RCC cells is a direct consequence of HIF activation. In contrast to TGF-alpha, other HIF targets, including vascular endothelial growth factor (VEGF), were unable to stimulate serum-independent growth of VHL(-/-) RCC cells. VHL(-/-) RCC cells expressing reintroduced type 2C mutants of VHL, and which retain the ability to degrade HIF, fail to overproduce TGF-alpha and proliferate in serum-free media. These data link HIF with the overproduction of a bona fide renal cell mitogen leading to activation of a pathway involved in growth of renal cancer cells. Moreover, our results suggest that HIF might be involved in oncogenesis to a much higher extent than previously appreciated.
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Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535
The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
Maxwell, P. H., Wiesener, M. S., Chang, G.-W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R., & Ratcliffe, P. J. (1999) · Nature · doi:10.1038/20459 · Cited by 5,180
HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2 Sensing
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin Jr., W. G. (2001) · Science · doi:10.1126/science.1059817 · Cited by 4,735
Regulation of Mammalian O 2 Homeostasis by Hypoxia-Inducible Factor 1
Semenza, G. L. (1999) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.15.1.551 · Cited by 1,914
Masson, N., Willam, C., Maxwell, P. H., Pugh, C. W., & Ratcliffe, P. J. (2001) · The EMBO Journal · doi:10.1093/emboj/20.18.5197 · Cited by 1,014
Molecular basis of the VHL hereditary cancer syndrome
Kaelin, W. G. (2002) · Nature Reviews Cancer · doi:10.1038/nrc885 · Cited by 865
A Specific Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase
Fry, D. W., Kraker, A. J., McMichael, A., Ambroso, L. A., Nelson, J. M., Leopold, W. R., Connors, R. W., & Bridges, A. J. (1994) · Science · doi:10.1126/science.8066447 · Cited by 806
HIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation
Yu, F., White, S. B., Zhao, Q., & Lee, F. S. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.181341498 · Cited by 796
Krieg, M., Haas, R., Brauch, H., Acker, T., Flamme, I., & Plate, K. H. (2000) · Oncogene · doi:10.1038/sj.onc.1203938 · Cited by 396
Clifford, S. C. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.10.1029 · Cited by 373
Cited by
HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression
Keith, B., Johnson, R. S., & Simon, M. C. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3183 · Cited by 1,693
Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy
Semenza, G. L. (2012) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2012.01.005 · Cited by 1,514
HIF-2α Promotes Hypoxic Cell Proliferation by Enhancing c-Myc Transcriptional Activity
Gordan, J. D., Bertout, J. A., Hu, C.-J., Diehl, J. A., & Simon, M. C. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.02.006 · Cited by 781
Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis
Kaur, B., Khwaja, F. W., Severson, E. A., Matheny, S. L., Brat, D. J., & Van Meir, E. G. (2005) · Neuro-Oncology · doi:10.1215/s1152851704001115 · Cited by 725
An oxygen-regulated switch in the protein synthesis machinery
Uniacke, J., Holterman, C. E., Lachance, G., Franovic, A., Jacob, M. D., Fabian, M. R., Payette, J., Holcik, M., Pause, A., & Lee, S. (2012) · Nature · doi:10.1038/nature11055 · Cited by 319
Self-citation
Metadata
- Authors
- Gunaratnam, L., Morley, M., Franovic, A., de Paulsen, N., Mekhail, K., Parolin, D. A. E., Nakamura, E., Lorimer, I. A. J., & Lee, S.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-11
- Volume
- 278
- Issue
- 45
- Pages
- 44966-44974
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2022694136
- Cited by
- 188
- References
- 10
- FWCI
- 6.01
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Gunaratnam, L., Morley, M., Franovic, A., de Paulsen, N., Mekhail, K., Parolin, D. A. E., Nakamura, E., Lorimer, I. A. J., & Lee, S. (2003). Hypoxia Inducible Factor Activates the Transforming Growth Factor-α/Epidermal Growth Factor Receptor Growth Stimulatory Pathway in VHL-/- Renal Cell Carcinoma Cells. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m305502200
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