Key role for activin B in cellular transformation after loss of the von Hippel-Lindau tumor suppressor.

Molecular and cellular biology (2009-01-23)
Ingrid Wacker, Martin Sachs, Karl Knaup, Michael Wiesener, Jörg Weiske, Otmar Huber, Ziya Akçetin, Jürgen Behrens
RESUMEN

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 beta 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.

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Monoclonal Anti-Activin B antibody produced in mouse, clone 146807, purified immunoglobulin

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