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Von Hippel–Lindau Disease
Von Hippel–Lindau Disease ER Maher, University of Birmingham, Birmingham, UK © 2013 Elsevier Inc. All rights reserved.
Glossary Hemagioblastoma A benign vascular tumor of the central nervous system. Kidney cancer A malignant tumor arising from the kidney.
Introduction Germline mutations in the VHL tumor suppressor gene most frequently cause von Hippel–Lindau (VHL) disease – an auto somal dominantly inherited familial cancer syndrome that is characterized by the development of vascular tumors in the retina and central nervous system (hemangioblastomas), clear cell renal cell carcinomas (RCCs), pheochromocytomas, pancreatic islet cell, and cysts in the kidney, pancreas, and epididymis. Germline VHL mutations may also present with familial pheochromocytoma and specific VHL missense mutations (when present in a homozygous or compound heterozygous state) can cause an autosomal recessive form of inherited polycythemia (characteristically Chuvash poly cythemia). Tumors from individuals with VHL demonstrate somatic inactivation of the wild-type allele (by loss of hetero zygosity, mutation, or promoter methylation), and so inactivation of both VHL alleles is required to initiate tumor igenesis. Most sporadic clear cell RCCs also demonstrate biallelic inactivation of the VHL tumor suppressor gene result ing from somatic loss/mutation/methylation. Reintroduction of wild-type VHL into a VHL protein (pVHL)-null RCC cell line suppresses tumor growth. The VHL gene product has multiple functions. However, the best characterized function is to regulate the proteosomal degradation of the α subunits of the hypoxia-inducible trans cription factors HIF-1 and HIF-2. Thus, the pVHL is a critical component of a ubiquitin ligase protein complex that binds to the α subunits of the HIF-1 and HIF-2 transcription factors and targets them for ubiquitylation and destruction in the
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Pheochromocytoma A tumor that arises from the adrenal medulla and usually secretes catecholamines such as epinephrine and norepinephrine. Polycythemia An excess of red blood cells. Tumor suppressor gene See antioncogene.
proteasome. Under normoxic conditions, the HIF-α subunits are rapidly degraded but oxygen is an essential cofactor for the proline hydroxylase (PHD) enzymes that must modify the HIF-α subunits for pVHL to bind and if pVHL is absent or unable to bind (e.g., if mutated or in hypoxia), the HIF-1 and HIF-2 transcription factors are stabilized and activate the hypoxic gene response. HIF-1 and HIF-2 target genes (particu larly HIF-2) are thought to have a key role not only in promoting angiogenesis but also in cell proliferation. Indeed, drugs that modulate the downstream targets of the pVHL/HIF pathway, including tyrosine kinase (sunitinib, sorafenib) and mammalian target of rapamycin (mTOR) inhibitors (e.g., tem sirolimus), have proven benefit in treating advanced kidney cancer.
See also: Tumor Suppressor Genes.
Further Reading Frew IJ and Krek W (2007) Multitasking by pVHL in tumour suppression. Current Opinion in Cell Biology 19: 685–690. Kaelin WG, Jr. (2009) Treatment of kidney cancer: Insights provided by the VHL tumor-suppressor protein. Cancer 115: 2262–2272.
Relevant Websites http://www.ncbi.nlm.nih.gov – GeneTests: GeneReviews. http://www.vhl.org – Von Hippel–Lindau Alliance (Patient Group).
Brenner’s Encyclopedia of Genetics, 2nd edition, Volume 7
doi:10.1016/B978-0-12-374984-0.01632-6
Glossary Hemagioblastoma A benign vascular tumor of the central nervous system. Kidney cancer A malignant tumor arising from the kidney.
Introduction Germline mutations in the VHL tumor suppressor gene most frequently cause von Hippel–Lindau (VHL) disease – an auto somal dominantly inherited familial cancer syndrome that is characterized by the development of vascular tumors in the retina and central nervous system (hemangioblastomas), clear cell renal cell carcinomas (RCCs), pheochromocytomas, pancreatic islet cell, and cysts in the kidney, pancreas, and epididymis. Germline VHL mutations may also present with familial pheochromocytoma and specific VHL missense mutations (when present in a homozygous or compound heterozygous state) can cause an autosomal recessive form of inherited polycythemia (characteristically Chuvash poly cythemia). Tumors from individuals with VHL demonstrate somatic inactivation of the wild-type allele (by loss of hetero zygosity, mutation, or promoter methylation), and so inactivation of both VHL alleles is required to initiate tumor igenesis. Most sporadic clear cell RCCs also demonstrate biallelic inactivation of the VHL tumor suppressor gene result ing from somatic loss/mutation/methylation. Reintroduction of wild-type VHL into a VHL protein (pVHL)-null RCC cell line suppresses tumor growth. The VHL gene product has multiple functions. However, the best characterized function is to regulate the proteosomal degradation of the α subunits of the hypoxia-inducible trans cription factors HIF-1 and HIF-2. Thus, the pVHL is a critical component of a ubiquitin ligase protein complex that binds to the α subunits of the HIF-1 and HIF-2 transcription factors and targets them for ubiquitylation and destruction in the
308
Pheochromocytoma A tumor that arises from the adrenal medulla and usually secretes catecholamines such as epinephrine and norepinephrine. Polycythemia An excess of red blood cells. Tumor suppressor gene See antioncogene.
proteasome. Under normoxic conditions, the HIF-α subunits are rapidly degraded but oxygen is an essential cofactor for the proline hydroxylase (PHD) enzymes that must modify the HIF-α subunits for pVHL to bind and if pVHL is absent or unable to bind (e.g., if mutated or in hypoxia), the HIF-1 and HIF-2 transcription factors are stabilized and activate the hypoxic gene response. HIF-1 and HIF-2 target genes (particu larly HIF-2) are thought to have a key role not only in promoting angiogenesis but also in cell proliferation. Indeed, drugs that modulate the downstream targets of the pVHL/HIF pathway, including tyrosine kinase (sunitinib, sorafenib) and mammalian target of rapamycin (mTOR) inhibitors (e.g., tem sirolimus), have proven benefit in treating advanced kidney cancer.
See also: Tumor Suppressor Genes.
Further Reading Frew IJ and Krek W (2007) Multitasking by pVHL in tumour suppression. Current Opinion in Cell Biology 19: 685–690. Kaelin WG, Jr. (2009) Treatment of kidney cancer: Insights provided by the VHL tumor-suppressor protein. Cancer 115: 2262–2272.
Relevant Websites http://www.ncbi.nlm.nih.gov – GeneTests: GeneReviews. http://www.vhl.org – Von Hippel–Lindau Alliance (Patient Group).
Brenner’s Encyclopedia of Genetics, 2nd edition, Volume 7
doi:10.1016/B978-0-12-374984-0.01632-6