Tid-1 interacts with the von Hippel-Lindau protein and modulates angiogenesis by destabilization of HIF-1α

The von Hippel-Lindau protein (pVHL) is a major tumor suppressor protein and also associated with the inhibition of angiogenesis via HIF-1α ubiquitination and proteasomal degradation. To further elucidate the biological activity of pVHL in angiogenesis, pVHL-interacting proteins were screened using the yeast two-hybrid system. We found that a mouse homologue of the long form of Drosophila tumor suppressor l(2)tid, Tid-1_L, directly interacts with pVHL in vitro and in vivo. Furthermore, Tid-1_L protein; enhanced the interaction between HIF-1α and pVHL, leading to the destabilisation of HIF-1α protein; therefore, Tid-1_L protein decreased vascular endothelial growth factor expression and inhibited angiogenesis in vivo and in vitro. These findings propose that Tid-1_L may play a critical role in pVHL-mediated tumor suppression by modulating the pVHL-dependent HIF-1α stability.