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. Author manuscript; available in PMC: 2022 Jul 20.
Published in final edited form as: J Genet Genomics. 2021 Jul 9;48(7):552–559. doi: 10.1016/j.jgg.2021.05.016

Fig. 1. The VHL-pVHL-E3-ccRCC axis.

Fig. 1.

The VHL gene is transcribed into the pVHL protein, which associates with several other proteins to form the E3 Ubiquitin Ligase complex. When a hydroxylated substrate is recognized, it is polyubiquitinated, which is a signal leading to degradation into oligonucleotides in the proteasome. This proline hydroxylation is crucial for recognition by the E3 complex, and the use of oxygen as a co-substrate in this step makes it sensitive to oxygen concentration. Under hypoxia (where oxygen is absent) or following VHL loss, this complex is no longer available to degrade its substrates in the usual way. When VHL loss (leading to overexpression of E3 complex substrates) is combined with the loss of other tumor-suppressing genes relating to epigenetic regulation, this leads kidney cells down a sure path leading to tumorigenesis and ccRCC. (p)VHL, von Hippel-Lindau tumor suppressor (protein); E2, Ubiquitin-conjugating enzyme; RBX1, RING-box protein 1; HIF-2, Hypoxia-inducible factor 2; EglN1, Egl nine homolog 1; TSG, tumor-suppressor gene; PBRM1, polybromo 1; BAP1, BRCA1-associated protein; SETD2, SET domain containing 2; ccRCC, clear cell renal cell carcinoma; U, ubiquitin; Pro, proline; Me, methyl group.