The heterodimeric transcription factor HIF is a key regulator of the hypoxic response, regulating the expression of a variety of genes, involved in the maintenance of the oxygen homeostasis. Under normoxic conditions, two proline residues within the HIFasubunit are hydroxylated by HIF prolyl-4-hydroxylase domain-containing enzymes (PHDs), which target HIFa for degradation by the ubiquitin-proteasome pathway. This is due to the dependency of PHDs on molecular oxygen as a co-substrate. In contrast, HIFa hydroxylation is inhibited in hypoxia, leading to the stabilization and activation of HIF. We recently identified the onconeural cerebellar degeneration-related protein 2 (Cdr2) as a novel interactor of PHD1 in two independent yeast two-hybrid screenings and confirmed these interaction by in vitro GST-pulldown assays. We demonstrated that Cdr2 mRNA expression is not regulated by oxygen but the protein levels are significantly elevated under hypoxic conditions, as well as upon PHD and proteasome inhibition in transiently transfected cells. Endogenous Cdr2 protein regulation was analyzed by newly generated polyclonal anti-Cdr2 antibodies and our data suggest that Cdr2 is hydroxylated at conserved proline clusters which culminates in oxygen-dependent protein regulation.