interaction with p53 explains a pro-proliferative function for vhl in cancer

The von hippel-lindau (vhl) protein binds and degrades hypoxia-inducible factors (hif) hydroxylated by prolyl-hydroxylases under normoxia. although originally described as a tumor suppressor, there is growing evidence that vhl paradoxically promote tumor growth. the significance of its described interactions with many other proteins remains unclear. we found that vhl interacts with p53, preventing its tetramerization, promoter binding and expression of its target genes p21, puma, and bax. vhl limited the decrease in proliferation and increase in apoptosis caused by p53 activation, independent of prolyl-hydroxylation and hif activity, and its presence in tumors caused a resistance to p53-inducing chemotherapy in vivo. we propose that vhl has both anti-tumor function, via hif degradation, and a new pro-tumor function via p53 target (p21, puma, bax) inhibition. because p53 plays a critical role in tumor biology, is activated by many chemotherapies, and because vhl levels vary among different tumors and its function can even be lost by mutations in some tumors, our results have important clinical applications.