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Molecular and Cellular Biology, April 2009, p. 1707-1718, Vol. 29, No. 7
0270-7306/09/$08.00+0     doi:10.1128/MCB.01184-07
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Key Role for Activin B in Cellular Transformation after Loss of the von Hippel-Lindau Tumor Suppressor {triangledown} ,{dagger}

Ingrid Wacker,1 Martin Sachs,1 Karl Knaup,1 Michael Wiesener,1 Jörg Weiske,2 Otmar Huber,2,{ddagger} Ziya Akçetin,3 and Jürgen Behrens1*

Nikolaus Fiebiger Center, University Erlangen-Nürnberg, Glückstr. 6, 91054 Erlangen, Germany,1 Department of Laboratory Medicine and Pathobiochemistry, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany,2 Department of Urology, Namik Kemal University, Tekirdag, Turkey3

Received 3 July 2007/ Returned for modification 8 October 2007/ Accepted 10 January 2009

The von Hippel-Lindau tumor suppressor gene (VHL) is mutated in clear cell renal cell carcinomas (RCC), leading to the activation of hypoxia-inducible factor (HIF)-mediated gene transcription. Several VHL/HIF targets, such as glycolysis, angiogenesis, cell growth, and chemotaxis of tumor cells, have been implicated in the transformed phenotype of RCC-regulating properties. Here, we show that VHL suppresses key features of cell transformation through downregulation of the HIF-dependent expression of activin B, a member of the transforming growth factor β superfamily. Activin B expression is repressed by restoration of VHL in VHL-deficient RCC cells and upregulated by hypoxia. RCC tumor samples show increased expression of activin B compared to that in the normal kidney. VHL increases cell adhesion to the extracellular matrix, promotes cell flattening, and reduces invasiveness. These effects are completely phenocopied by RNA interference-mediated knockdown of activin B and reverted by treatment with recombinant activin B. Finally, knockdown of activin B reduces tumor growth of RCC cells in nude mice. Our data indicate that activin B is a key mediator of VHL/HIF-induced transformation in RCC.

* Corresponding author. Mailing address: Nikolaus Fiebiger Center, University Erlangen-Nürnberg, Glückstr. 6, 91054 Erlangen, Germany. Phone: 49-9131-8529109. Fax: 49-9131-8529111. E-mail: jbehrens{at}molmed.uni-erlangen.de

{triangledown} Published ahead of print on 21 January 2009.

{dagger} Supplemental data for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Institute for Biochemistry, University of Jena, Nonnenplan 2, 07743 Jena, Germany.

Molecular and Cellular Biology, April 2009, p. 1707-1718, Vol. 29, No. 7
0270-7306/09/$08.00+0     doi:10.1128/MCB.01184-07
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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