期刊
ONCOGENE
卷 20, 期 3, 页码 395-398出版社
SPRINGERNATURE
DOI: 10.1038/sj.onc.1204055
关键词
p53; VHL; HIF-1 alpha; mdm-2; beta-catenin
Recently it has been shown that the VHL tumor suppressor targets the hypoxia-inducible transcription factor (HIF-1) for ubiquitin-dependent degradation by the proteasome, Past mysteries of the p53 tumor suppressor help to solve 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, establishing 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 accumulation transcriptionally active HIF-1 and p53, More detailed analysis depicts 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. The extended model proposes that an oncoprotein and a tumor suppressor due to transactivation coupled with feedback protein degradation might form functional pairs (Rb/E7, E2F/Rb, E2F/Mdm-2, catenin/APC, p27, cyclin D1, Rb/gankyrin), thus, predicting missing links.
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