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

Oncogene
M V Blagosklonny

Abstract

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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Citations

Nov 21, 2012·Briefings in Functional Genomics·A Kristine Jolliffe, W Brent Derry
Sep 12, 2013·PloS One·Kun TianJean-Marc Schwartz
Jan 29, 2003·Proceedings of the National Academy of Sciences of the United States of America·Katrina M ComerfordCormac T Taylor
May 25, 2005·Liver International : Official Journal of the International Association for the Study of the Liver·Lu TanHong-Yang Wang
May 10, 2005·Human Mutation·Jacques S BeckmannLaurent Falquet
Jun 18, 2005·Journal of Cellular Biochemistry·Jörn KarhausenSean P Colgan
Aug 12, 2004·Biochemical and Biophysical Research Communications·Yan XueDaiming Fan
Nov 25, 2004·Diabetes·Sergiu-Bogdan CatrinaLorenz Poellinger
Feb 28, 2003·The Journal of Biological Chemistry·Delin ChenWei Gu
Jan 8, 2014·The Journal of Biological Chemistry·James BagnallViolaine Sée
May 10, 2021·Materials Science & Engineering. C, Materials for Biological Applications·Ruijiang LiuShasha Li

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