Do VHL and HIF-1 mirror p53 and Mdm-2? Degradation-transactivation loops of oncoproteins and tumor suppressors

Recently it has been shown that the VHL tumor suppressor targets the hypoxi a-inducible transcription factor (HIF-1) for ubiquitin-dependent degradatio n by the proteasome, Past mysteries of the p53 tumor suppressor help to sol ve the present puzzles of the VHL tumor suppressor. Thus, Mdm-2 targets the p53 tumor suppressor for ubiquitin-dependent degradation by the proteasome , but, in addition, the p53 transcription factor induces Mdm-2, thus, estab lishing a feedback loop. Hypoxia or DNA damage by abrogating binding of HIF -1 with VHL and p53 with Mdm-2, respectively, leads to stabilization and ac cumulation transcriptionally active HIF-1 and p53, More detailed analysis d epicts the VHL/HIF-1 pair as the p53/mdm-2 pair that is turned upside down, suggesting that VHL may be a HIF-1-inducible gene of the feedback loop. Th e extended model proposes that an oncoprotein and a tumor suppressor due to transactivation coupled with feedback protein degradation might form funct ional pairs (Rb/E7, E2F/Rb, E2F/Mdm-2, catenin/APC, p27, cyclin D1, Rb/gank yrin), thus, predicting missing links.