Hypoxia-inducible factor underlies von Hippel-Lindau disease stigmata

Abstract

von Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome that causes a predisposition to renal clear-cell carcinoma, hemangioblastoma, pheochromocytoma, and autosomal-recessive familial polycythemia. pVHL is the substrate conferring subunit of an E3 ubiquitin ligase complex that binds to the three hypoxia-inducible factor alpha subunits (HIF1-3α) for polyubiquitylation under conditions of normoxia, targeting them for immediate degradation by the proteasome. Certain mutations in pVHL have been determined to be causative of VHL disease through the disruption of HIFα degradation. However, it remains a focus of investigation and debate whether the disruption of HIFα degradation alone is sufficient to explain the complex genotype-phenotype relationship of VHL disease or whether the other lesser or yet characterized substrates and functions of pVHL impact the development of the VHL disease stigmata; the elucidation of which would have a significant ramification to the direction of research efforts and future management and care of VHL patients and for those manifesting sporadic counterparts of VHL disease. Here, we examine the current literature including the other emergent pseudohypoxic diseases and propose that the VHL disease-phenotypic spectrum could be explained solely by the varied disruption of HIFα signaling upon the loss or mutation in pVHL.

Keywords: HIF; PHD; VHL; cancer biology; hypoxia; oxygen-sensing; pseudohypoxic diseases.

Figure 1.. The canonical regulatory components of the metazoan oxygen-sensing pathway.

The dotted line connected to the solved HIFα fragment represents the unstructured C-terminal region of HIFα, which contains the oxygen dependent degradation domain. PDB codes of structures used to construct the protein depictions are 4ZP4 (HIF2α+HIFβ), 4ZPK (HIF2α+HIFβ+Hypoxia-response element), 5L9B (PHD2), 5N4W (Cul2 +Rbx1+EloB + EloC+pVHL), and 3ZRF (EloB +EloC + pVHL). The structural representation of the pVHL-E3 ubiquitin ligase complex was constructed by aligning structures 5N4W and 3ZRF and keeping the most complete model of each duplicated subunit.

Figure 2.. HIF-centric unifying model of VHL and other pseudohypoxic diseases.

See text for details. VHL, Elongin B, Elongin C (PDB:1VCB); HIF2α C-Terminal PAS Domain (PDB:3F1P); HIF1α C-Terminal PAS Domain (PDB:4ZPR); PHD2 Catalytic Core (PDB: 5L9B).