Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Identification of membrane type-1 matrix metalloproteinase as a target of hypoxia-inducible factor-2α in von Hippel–Lindau renal cell carcinoma

Abstract

Metastatic renal cell carcinoma (RCC) resulting from the hereditary loss of the von Hippel–Lindau (VHL) tumor suppressor gene is the leading cause of death in VHL patients due to the deleterious effects of the metastatic tumor(s). VHL functions in the destruction of the alpha subunits of the heterodimeric transcription factor, hypoxia-inducible factor (HIF-1α and HIF-2α), in normoxic conditions. When VHL function is lost, HIF-α protein is stabilized, and target hypoxia-inducible genes are transcribed. The process of tumor invasion and metastasis involves the destruction of the extracellular matrix, which is accomplished primarily by the matrix metalloproteinase (MMP) family of enzymes. Here, we describe a connection between the loss of VHL tumor suppressor function and the upregulation of membrane type-1 MMP (MT1-MMP) gene expression and protein. Specifically, MT1-MMP is upregulated in VHL−/− RCC cells through an increase in gene transcription, which is mediated by the cooperative effects of the transcription factors, HIF-2 and Sp1. Further, we identify a functional HIF-binding site in the proximal promoter of MT1-MMP. To our knowledge, this is the first report to show direct regulation of MT1-MMP by HIF-2 and to provide a direct link between the loss of VHL tumor suppressor function and an increase in MMP gene and protein expression.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Annabi B, Lee YT, Turcotte S, Naud E, Desrosiers RR, Champagne M, Eliopoulos N, Galipeau J and Beliveau R . (2003). Stem. Cells, 21, 337–347.

  • Barry RE and Krek W . (2004). Trends Mol. Med., 10, 466–472.

  • Bartolome RA, Galvez BG, Longo N, Baleux F, Van Muijen GN, Sanchez-Mateos P, Arroyo AG and Teixido J . (2004). Cancer Res., 64, 2534–2543.

  • Bogenrieder T and Herlyn M . (2003). Oncogene, 22, 6524–6536.

  • Egeblad M and Werb Z . (2002). Nat. Rev. Cancer, 2, 161–174.

  • Gaidarova S and Jimenez SA . (2002). J. Biol. Chem., 277, 38737–38745.

  • Giatromanolaki A, Koukourakis MI, Sivridis E, Turley H, Talks K, Pezzella F, Gatter KC and Harris AL . (2001). Br. J. Cancer, 85, 881–890.

  • Harris AL . (2002). Nat. Rev. Cancer, 2, 38–47.

  • Hes FJ, van der Luijt RB and Lips CJ . (2001). Neth. J. Med., 59, 225–234.

  • Hotary K, Allen E, Punturieri A, Yana I and Weiss SJ . (2000). J. Cell. Biol., 149, 1309–1323.

  • Hotary KB, Allen ED, Brooks PC, Datta NS, Long MW and Weiss SJ . (2003). Cell, 114, 33–45.

  • Iida J, Wilhelmson KL, Price MA, Wilson CM, Pei D, Furcht LT and McCarthy JB . (2004). J. Invest. Dermatol., 122, 167–176.

  • Iliopoulos O, Kibel A, Gray S and Kaelin Jr WG . (1995). Nat. Med., 1, 822–826.

  • Jain S, Maltepe E, Lu MM, Simon C and Bradfield CA . (1998). Mech. Dev., 73, 117–123.

  • Jiang BH, Rue E, Wang GL, Roe R and Semenza GL . (1996). J. Biol. Chem., 271, 17771–17778.

  • Kaelin Jr WG . (2002). Nat. Rev. Cancer, 2, 673–682.

  • Kitagawa Y, Kunimi K, Uchibayashi T, Sato H and Namiki M . (1999). J. Urol., 162, 905–909.

  • Kondo K, Kim WY, Lechpammer M and Kaelin Jr WG . (2003). PLoS Biol., 1, E83.

  • Kondo K, Klco J, Nakamura E, Lechpammer M and Kaelin Jr WG . (2002a). Cancer Cell, 1, 237–246.

  • Kondo S, Kubota S, Shimo T, Nishida T, Yosimichi G, Eguchi T, Sugahara T and Takigawa M . (2002b). Carcinogenesis, 23, 769–776.

  • Koochekpour S, Jeffers M, Wang PH, Gong C, Taylor GA, Roessler LM, Stearman R, Vasselli JR, Stetler-Stevenson WG, Kaelin Jr WG, Linehan WM, Klausner RD, Gnarra JR and Vande Woude GF . (1999). Mol. Cell. Biol., 19, 5902–5912.

  • Lehti K, Lohi J, Valtanen H and Keski-Oja J . (1998). Biochem. J., 334 (Part 2), 345–353.

  • Linehan WM, Walther MM and Zbar B . (2003). J. Urol., 170, 2163–2172.

  • Lohi J, Lehti K, Valtanen H, Parks WC and Keski-Oja J . (2000). Gene, 242, 75–86.

  • Maher ER and Kaelin Jr WG . (1997). Medicine (Baltimore), 76, 381–391.

  • Maquoi E, Sounni NE, Devy L, Olivier F, Frankenne F, Krell HW, Grams F, Foidart JM and Noel A . (2004). Clin. Cancer Res., 10, 4038–4047.

  • Maranchie JK, Vasselli JR, Riss J, Bonifacino JS, Linehan WM and Klausner RD . (2002). Cancer Cell., 1, 247–255.

  • Martin B, Vaquero A, Priebe W and Portugal J . (1999). Nucleic Acids Res., 27, 3402–3409.

  • Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER and Ratcliffe PJ . (1999). Nature, 399, 271–275.

  • McCawley LJ and Matrisian LM . (2001). Curr. Opin. Cell. Biol., 13, 534–540.

  • Miki N, Ikuta M and Matsui T . (2004). J. Biol. Chem., 279, 15025–15031.

  • Mori H, Tomari T, Koshikawa N, Kajita M, Itoh Y, Sato H, Tojo H, Yana I and Seiki M . (2002). EMBO J., 21, 3949–3959.

  • Ottino P, Finley J, Rojo E, Ottlecz A, Lambrou GN, Bazan HE and Bazan NG . (2004). Mol. Vis., 10, 341–350.

  • Richards FM, Webster AR, McMahon R, Woodward ER, Rose S and Maher ER . (1998). J. Intern. Med., 243, 527–533.

  • Sanchez-Elsner T, Botella LM, Velasco B, Langa C and Bernabeu C . (2002). J. Biol. Chem., 277, 43799–43808.

  • Sanchez-Elsner T, Ramirez JR, Sanz-Rodriguez F, Varela E, Bernabeu C and Botella LM . (2004). J. Mol. Biol., 336, 9–24.

  • Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E and Seiki M . (1994). Nature, 370, 61–65.

  • Seiki M . (2003). Cancer Lett., 194, 1–11.

  • Singh AD, Shields CL and Shields JA . (2001). Surv. Ophthalmol., 46, 117–142.

  • Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ and Krek W . (2003). Nature, 425, 307–311.

  • Strongin AY, Collier I, Bannikov G, Marmer BL, Grant GA and Goldberg GI . (1995). J. Biol. Chem., 270, 5331–5338.

  • Tian H, McKnight SL and Russell DW . (1997). Genes Dev., 11, 72–82.

  • Ueda J, Kajita M, Suenaga N, Fujii K and Seiki M . (2003). Oncogene, 22, 8716–8722.

  • Visse R and Nagase H . (2003). Circ. Res., 92, 827–839.

  • Wiesener MS, Turley H, Allen WE, Willam C, Eckardt KU, Talks KL, Wood SM, Gatter KC, Harris AL, Pugh CW, Ratcliffe PJ and Maxwell PH . (1998). Blood, 92, 2260–2268.

  • Zimmer M, Doucette D, Siddiqui N and Iliopoulos O . (2004). Mol. Cancer Res., 2, 89–95.

Download references

Acknowledgements

This work was supported by the National Institutes of Health grants AR-26599 (CEB) and CA-77267 (CEB), by a grant from the Milheim Foundation for Cancer Research #2003-9 (BLP), and by the Academy of Finland and the Finnish Cancer Foundation (JL). BLP is supported by a pre-doctoral fellowship from NIH (T32-AI07363).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Constance E Brinckerhoff.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Petrella, B., Lohi, J. & Brinckerhoff, C. Identification of membrane type-1 matrix metalloproteinase as a target of hypoxia-inducible factor-2α in von Hippel–Lindau renal cell carcinoma. Oncogene 24, 1043–1052 (2005). https://doi.org/10.1038/sj.onc.1208305

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208305

Keywords

This article is cited by

Search

Quick links