Von Hippel–Lindau disease: insights into oxygen sensing, protein degradation, and cancer
Germline loss-of-function mutations of the VHL tumor suppressor gene cause von Hippel–Lindau disease, which is associated with an increased risk of hemangioblastomas, clear cell renal cell carcinomas (ccRCCs), and paragangliomas. This Review describes mechanisms involving the VHL gene product in oxy...
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2022-09-01
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| Series: | The Journal of Clinical Investigation |
| Online Access: | https://doi.org/10.1172/JCI162480 |
| _version_ | 1797634552580014080 |
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| author | William G. Kaelin Jr. |
| author_facet | William G. Kaelin Jr. |
| author_sort | William G. Kaelin Jr. |
| collection | DOAJ |
| description | Germline loss-of-function mutations of the VHL tumor suppressor gene cause von Hippel–Lindau disease, which is associated with an increased risk of hemangioblastomas, clear cell renal cell carcinomas (ccRCCs), and paragangliomas. This Review describes mechanisms involving the VHL gene product in oxygen sensing, protein degradation, and tumor development and current therapeutic strategies targeting these mechanisms. The VHL gene product is the substrate recognition subunit of a ubiquitin ligase that targets the α subunit of the heterodimeric hypoxia-inducible factor (HIF) transcription factor for proteasomal degradation when oxygen is present. This oxygen dependence stems from the requirement that HIFα be prolyl-hydroxylated on one (or both) of two conserved prolyl residues by members of the EglN (also called PHD) prolyl hydroxylase family. Deregulation of HIF, and particularly HIF2, drives the growth of VHL-defective ccRCCs. Drugs that inhibit the HIF-responsive gene product VEGF are now mainstays of ccRCC treatment. An allosteric HIF2 inhibitor was recently approved for the treatment of ccRCCs arising in the setting of VHL disease and has advanced to phase III testing for sporadic ccRCCs based on promising phase I/II data. Orally available EglN inhibitors are being tested for the treatment of anemia and ischemia. Five of these agents have been approved for the treatment of anemia in the setting of chronic kidney disease in various countries around the world. |
| first_indexed | 2024-03-11T12:09:21Z |
| format | Article |
| id | doaj.art-003da503ec7544aeab4bc42bebe35058 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:09:21Z |
| publishDate | 2022-09-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-003da503ec7544aeab4bc42bebe350582023-11-07T16:19:20ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-09-0113218Von Hippel–Lindau disease: insights into oxygen sensing, protein degradation, and cancerWilliam G. Kaelin Jr.Germline loss-of-function mutations of the VHL tumor suppressor gene cause von Hippel–Lindau disease, which is associated with an increased risk of hemangioblastomas, clear cell renal cell carcinomas (ccRCCs), and paragangliomas. This Review describes mechanisms involving the VHL gene product in oxygen sensing, protein degradation, and tumor development and current therapeutic strategies targeting these mechanisms. The VHL gene product is the substrate recognition subunit of a ubiquitin ligase that targets the α subunit of the heterodimeric hypoxia-inducible factor (HIF) transcription factor for proteasomal degradation when oxygen is present. This oxygen dependence stems from the requirement that HIFα be prolyl-hydroxylated on one (or both) of two conserved prolyl residues by members of the EglN (also called PHD) prolyl hydroxylase family. Deregulation of HIF, and particularly HIF2, drives the growth of VHL-defective ccRCCs. Drugs that inhibit the HIF-responsive gene product VEGF are now mainstays of ccRCC treatment. An allosteric HIF2 inhibitor was recently approved for the treatment of ccRCCs arising in the setting of VHL disease and has advanced to phase III testing for sporadic ccRCCs based on promising phase I/II data. Orally available EglN inhibitors are being tested for the treatment of anemia and ischemia. Five of these agents have been approved for the treatment of anemia in the setting of chronic kidney disease in various countries around the world.https://doi.org/10.1172/JCI162480 |
| spellingShingle | William G. Kaelin Jr. Von Hippel–Lindau disease: insights into oxygen sensing, protein degradation, and cancer The Journal of Clinical Investigation |
| title | Von Hippel–Lindau disease: insights into oxygen sensing, protein degradation, and cancer |
| title_full | Von Hippel–Lindau disease: insights into oxygen sensing, protein degradation, and cancer |
| title_fullStr | Von Hippel–Lindau disease: insights into oxygen sensing, protein degradation, and cancer |
| title_full_unstemmed | Von Hippel–Lindau disease: insights into oxygen sensing, protein degradation, and cancer |
| title_short | Von Hippel–Lindau disease: insights into oxygen sensing, protein degradation, and cancer |
| title_sort | von hippel lindau disease insights into oxygen sensing protein degradation and cancer |
| url | https://doi.org/10.1172/JCI162480 |
| work_keys_str_mv | AT williamgkaelinjr vonhippellindaudiseaseinsightsintooxygensensingproteindegradationandcancer |