The hypoxia-inducible heterodimeric transcription factor HIF is the master regulator of the hypoxic response in eukaryotic cells. Prolyl-4-hydroxylase domain-containing (PHD1-3) and asparaginyl hydroxylase (FIH) enzymes regulate the stability and transcriptional activity of HIF-a subunits by oxygen-dependent hydroxylation of prolyl and asparaginyl residues, respectively. We asked whether these iron-dependent dioxygenases have alternative substrates other than HIF-a. By yeast two-hybrid screening, we have identified several PHD1 interacting proteins, including the onconeural antigen cerebellar degeneration-related 2 (Cdr2) protein and TRIM37, a member of the tripartite motif protein family. Cdr2 is associated with paraneoplastic syndromes in which neoplastic expression of Cdr2, especially in breast and ovarian cancer patients, triggers an autoimmune response that culminates in cerebellar degeneration. Mulibrey (Muscle-liver- brain-eye) nanism is a rare autosomal recessive growth disorder caused by mutations in TRIM37 that encodes for a RING finger ubiquitin E3 ligase. By transient transfection assays in HeLa cells, we could demonstrate that the protein levels of both Cdr2 and TRIM37 are stabilized under hypoxia, PHD as well as proteasome inhibition. Studies are now in progress to investigate the post- translational modification of Cdr2 and TRIM37 by PHD1.