Normal biology of the VHL-HIF axis in the setting of (A) normoxia and (B) hypoxia

Normal biology of the VHL-HIF axis in the setting of (A) normoxia and (B) hypoxia. In normoxic conditions, HIFα is hydroxylated on specific proline residues by prolyl-hydroxylases. VHL acts as the sensor for these hydroxylated proline residues as part of the VHL-E3 ubiquitin ligase. This polyubiquitinates HIFα and marks it for degradation by the proteasome. In hypoxic conditions (or in the presence of aberrant VHL), HIFα is allowed to accumulate in the cell. (C) It associates with HIFβ, and this complex translocates to the nucleus and acts as a transcription factor binding to hypoxia response elements and up-regulating oxygen sensitive genes. These include vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor alpha (TGFα), glucose transporter-1 (GLUT1), carbonic anhydrase IX (CA-IX), erythropoietin (EPO), and others. Examples of certain ligands’ receptors are given, including VEGF receptor (VEGFR), PDGF receptor (PDGFR), and the receptor for TNFα, epidermal growth factor receptor (EGFR). Shown is the downstream signaling for 1 of these receptors, VEGFR, including through the PI3 kinase (PI3K)/AKT/mTOR, p38 MAP kinase (p38MAPK), and RAS/RAF/MEK/ERK pathways. Examples of agents that impact on this cascade are given, and where they act on the pathway is shown.

Publication

The von Hippel-Lindau Gene. () Peter E. Clark, et al. Cancer. ;113(7 Suppl):1768-1778. Figure: F1. All organisms Drosophila melanogaster Homo sapiens

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