Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor

Abstract Hemangioblastomas are highly vascular tumors of the central nervous system that overexpress the hypoxia-inducible gene, vascular endothelial growth factor (VEGF), as a consequence of mutational inactivation of the von Hippel-Lindau tumor suppressor gene (VHL). Previous reports showed that hemangioblastomas can also express erythropoietin (Epo), which is also hypoxia-inducible. However, Epo expression in hemangioblastomas was observed only in individual cases, and the analyses were mainly based on indirect determination of erythropoiesis-stimulating activity. Therefore, we analyzed a series of 11 hemangioblastomas for Epo, VEGF, and VHL expression by Northern blot analysis and compared the results with normal brain and glioblastomas. Surprisingly, we observed Epo mRNA expression in all hemangioblastoma specimens analyzed, but in none of four glioblastomas. In contrast, VEGF mRNA was expressed in all hemangioblastomas and all glioblastomas. In situ hybridization revealed neoplastic stromal cells as Epo- and VEGF-producing cells in hemangioblastomas. These results suggest that in the nonhypoxic microenvironment of hemangioblastoma, Epo, similar to VEGF, might be negatively regulated by the VHL gene product. © 1998 by The American Society of Hematology.

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Coexpression of Erythropoietin and Vascular Endothelial Growth Factor in Nervous System Tumors Associated With von Hippel-Lindau Tumor Suppressor Gene Loss of Function

Blood ◽

10.1182/blood.v92.9.3388.421a09_3388_3393 ◽

1998 ◽

Vol 92 (9) ◽

pp. 3388-3393 ◽

Cited By ~ 6

Author(s):

Marion Krieg ◽

Hugo H. Marti ◽

Karl H. Plate

Keyword(s):

Vascular Endothelial Growth Factor ◽

Nervous System ◽

Growth Factor ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Suppressor Gene ◽

Vascular Tumors ◽

Vascular Endothelial ◽

Von Hippel Lindau ◽

Endothelial Growth Factor

Hemangioblastomas are highly vascular tumors of the central nervous system that overexpress the hypoxia-inducible gene, vascular endothelial growth factor (VEGF), as a consequence of mutational inactivation of the von Hippel-Lindau tumor suppressor gene (VHL). Previous reports showed that hemangioblastomas can also express erythropoietin (Epo), which is also hypoxia-inducible. However, Epo expression in hemangioblastomas was observed only in individual cases, and the analyses were mainly based on indirect determination of erythropoiesis-stimulating activity. Therefore, we analyzed a series of 11 hemangioblastomas for Epo, VEGF, and VHL expression by Northern blot analysis and compared the results with normal brain and glioblastomas. Surprisingly, we observed Epo mRNA expression in all hemangioblastoma specimens analyzed, but in none of four glioblastomas. In contrast, VEGF mRNA was expressed in all hemangioblastomas and all glioblastomas. In situ hybridization revealed neoplastic stromal cells as Epo- and VEGF-producing cells in hemangioblastomas. These results suggest that in the nonhypoxic microenvironment of hemangioblastoma, Epo, similar to VEGF, might be negatively regulated by the VHL gene product. © 1998 by The American Society of Hematology.

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Faculty Opinions recommendation of The von Hippel-Lindau tumor suppressor protein mediates ubiquitination of activated atypical protein kinase C.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1002435.25855 ◽

2001 ◽

Author(s):

Eamonn Maher

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Tumor Suppressor ◽

Tumor Suppressor Protein ◽

Atypical Protein Kinase C ◽

Atypical Protein Kinase ◽

Von Hippel Lindau ◽

Kinase C

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Von Hippel-Lindau Tumor Suppressor Pathways & Corresponding Therapeutics in Kidney Cancer

Journal of Genetics and Genomics ◽

10.1016/j.jgg.2021.05.016 ◽

2021 ◽

Author(s):

Maxwell Shulman ◽

Rachel Shi ◽

Qing Zhang

Keyword(s):

Tumor Suppressor ◽

Kidney Cancer ◽

Von Hippel Lindau

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Inactivation of the Arylhydrocarbon Receptor Nuclear Translocator (Arnt) Suppresses von Hippel-Lindau Disease-Associated Vascular Tumors in Mice

Molecular and Cellular Biology ◽

10.1128/mcb.25.8.3163-3172.2005 ◽

2005 ◽

Vol 25 (8) ◽

pp. 3163-3172 ◽

Cited By ~ 112

Author(s):

Erinn B. Rankin ◽

Debra F. Higgins ◽

Jacqueline A. Walisser ◽

Randall S. Johnson ◽

Christopher A. Bradfield ◽

...

Keyword(s):

Transcription Factors ◽

Germ Line ◽

Hypoxia Inducible Factor ◽

Suppressor Gene ◽

Vascular Tumors ◽

Von Hippel Lindau ◽

Von Hippel Lindau Disease ◽

Arylhydrocarbon Receptor ◽

Vhl Disease ◽

Endothelial Growth Factor

ABSTRACT Patients with germ line mutations in the VHL tumor suppressor gene are predisposed to the development of highly vascularized tumors within multiple tissues. Loss of pVHL results in constitutive activation of the transcription factors HIF-1 and HIF-2, whose relative contributions to the pathogenesis of the VHL phenotype have yet to be defined. In order to examine the role of HIF in von Hippel-Lindau (VHL)-associated vascular tumorigenesis, we utilized Cre-loxP-mediated recombination to inactivate hypoxia-inducible factor-1α (Hif-1α) and arylhydrocarbon receptor nuclear translocator (Arnt) genes in a VHL mouse model of cavernous liver hemangiomas and polycythemia. Deletion of Hif-1α did not affect the development of vascular tumors and polycythemia, nor did it suppress the increased expression of vascular endothelial growth factor (Vegf) and erythropoietin (Epo). In contrast, phosphoglycerokinase (Pgk) expression was substantially decreased, providing evidence for target gene-dependent functional redundancy between different Hif transcription factors. Inactivation of Arnt completely suppressed the development of hemangiomas, polycythemia, and Hif-induced gene expression. Here, we demonstrate genetically that the development of VHL-associated vascular tumors in the liver depends on functional ARNT. Furthermore, we provide evidence that individual HIF transcription factors may play distinct roles in the development of specific VHL disease manifestations.

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Hydrogen Sulfide Increases Hypoxia-inducible Factor-1 Activity Independently of von Hippel–Lindau Tumor Suppressor-1 inC. elegans

Molecular Biology of the Cell ◽

10.1091/mbc.e09-03-0199 ◽

2010 ◽

Vol 21 (1) ◽

pp. 212-217 ◽

Cited By ~ 58

Author(s):

Mark W. Budde ◽

Mark B. Roth

Keyword(s):

Hydrogen Sulfide ◽

Tumor Suppressor ◽

Environmental Changes ◽

Hypoxia Inducible Factor ◽

Low Oxygen ◽

Animal Cells ◽

Von Hippel Lindau ◽

C Elegans ◽

Reporter Activity ◽

And Behavior

Rapid alteration of gene expression in response to environmental changes is essential for normal development and behavior. The transcription factor hypoxia-inducible factor (HIF)-1 is well known to respond to alterations in oxygen availability. In nature, low oxygen environments are often found to contain high levels of hydrogen sulfide (H2S). Here, we show that Caenorhabditis elegans can have mutually exclusive responses to H2S and hypoxia, both involving HIF-1. Specifically, H2S results in HIF-1 activity throughout the hypodermis, whereas hypoxia causes HIF-1 activity in the gut as judged by a reporter for HIF-1 activity. C. elegans require hif-1 to survive in room air containing trace amounts of H2S. Exposure to H2S results in HIF-1 nuclear localization and transcription of HIF-1 targets. The effects of H2S on HIF-1 reporter activity are independent of von Hippel–Lindau tumor suppressor (VHL)-1, whereas VHL-1 is required for hypoxic regulation of HIF-1 reporter activity. Because H2S is naturally produced by animal cells, our results suggest that endogenous H2S may influence HIF-1 activity.

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