VHL and neoplasm: Our findings support a model in which RSUME is not downregulated in presence of VHL mutants, achieving high RSUME expression in specific tissues, were RSUME becomes critical for potentiating the missense VHL loss of function on HIF-2-α degradation, providing a permissive setting for the development of VHL tumors and promoting deregulated angiogenesis needed for tumor progression (Fig. 6).