CALCR and neoplasm: VHL encodes a tumor suppressor, which possesses E3 ubiquitin activity in complex with the scaffold proteins EloB/C, Cul2 and Rox1a/Rbx1.194 In clear cell renal cell carcinoma, VHL activity is suppressed, resulting in the accumulation of the transcription factor Hif-1α in response to hypoxia.195 Hypoxia has been found to stimulate copper uptake via increasing CTR1 expression through the hypoxia-induced factor pathway.196–198 In Drosophila, we found that Vhl functions differently in different tissues, influencing melanin formation by altering copper levels via Ctr1A.