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Tid-1 Interacts with the von Hippel-Lindau Protein and Modulates Angiogenesis by Destabilization of HIF-1

¹ Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea; Colleges of ² Dentistry and ³ Medicine, Pusan National University, Busan, Korea; and ⁴ Department of Laboratory Medicine and Pathology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

Requests for reprints: Kyu-Won Kim, College of Pharmacy, Seoul National University, Seoul 151-742, Korea. Phone: 82-2-880-6988; Fax: 82-2-872-1795; E-mail: qwonkim{at}plaza.snu.ac.kr.

The von Hippel-Lindau protein (pVHL) is a major tumor suppressor protein and also associated with the inhibition of angiogenesis via HIF-1 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-1 and pVHL, leading to the destabilization of HIF-1 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-1 stability.

Key Words: Tid-1 • pVHL • angiogenesis • HIF-1 • yeast two-hybrid

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