Proteostasis Modulators Prolong Missense VHL Protein Activity and Halt Tumor Progression
Although missense mutations of the von Hippel-Lindau disease (VHL) gene are the most common germline mutation underlying this heritable cancer syndrome, the mechanism of tumorigenesis is unknown. We found a quantitative reduction of missense mutant VHL protein (pVHL) in tumors associated with physio...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2013-01-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124712004329 |
| _version_ | 1828907826137792512 |
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| author | Chunzhang Yang Kristin Huntoon Alexander Ksendzovsky Zhengping Zhuang Russell R. Lonser |
| author_facet | Chunzhang Yang Kristin Huntoon Alexander Ksendzovsky Zhengping Zhuang Russell R. Lonser |
| author_sort | Chunzhang Yang |
| collection | DOAJ |
| description | Although missense mutations of the von Hippel-Lindau disease (VHL) gene are the most common germline mutation underlying this heritable cancer syndrome, the mechanism of tumorigenesis is unknown. We found a quantitative reduction of missense mutant VHL protein (pVHL) in tumors associated with physiologic mRNA expression. Although mutant pVHL is unstable and degraded contemporarily with translation, it retains its E3 ligase function, including hypoxia-inducible factor degradation. The premature pVHL degradation is due to misfolding and imbalance of chaperonin binding. Histone deacetylase inhibitors (HDACIs) can modulate this pathway by inhibiting the HDAC-Hsp90 chaperone axis, stabilizing pVHL, and restoring activity comparable to wild-type protein, both in vitro and in animal models. Furthermore, HDACI-mediated stabilization of missense pVHL significantly attenuates the growth of 786-O rodent tumor model. These findings provide direct biological insight into VHL-associated tumors and elucidate a treatment paradigm for VHL. |
| first_indexed | 2024-12-13T18:00:00Z |
| format | Article |
| id | doaj.art-3f84117a938840dd9bc25f15da79783c |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-13T18:00:00Z |
| publishDate | 2013-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-3f84117a938840dd9bc25f15da79783c2022-12-21T23:36:14ZengElsevierCell Reports2211-12472013-01-0131525910.1016/j.celrep.2012.12.007Proteostasis Modulators Prolong Missense VHL Protein Activity and Halt Tumor ProgressionChunzhang Yang0Kristin Huntoon1Alexander Ksendzovsky2Zhengping Zhuang3Russell R. Lonser4Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USASurgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USASurgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USASurgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USASurgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USAAlthough missense mutations of the von Hippel-Lindau disease (VHL) gene are the most common germline mutation underlying this heritable cancer syndrome, the mechanism of tumorigenesis is unknown. We found a quantitative reduction of missense mutant VHL protein (pVHL) in tumors associated with physiologic mRNA expression. Although mutant pVHL is unstable and degraded contemporarily with translation, it retains its E3 ligase function, including hypoxia-inducible factor degradation. The premature pVHL degradation is due to misfolding and imbalance of chaperonin binding. Histone deacetylase inhibitors (HDACIs) can modulate this pathway by inhibiting the HDAC-Hsp90 chaperone axis, stabilizing pVHL, and restoring activity comparable to wild-type protein, both in vitro and in animal models. Furthermore, HDACI-mediated stabilization of missense pVHL significantly attenuates the growth of 786-O rodent tumor model. These findings provide direct biological insight into VHL-associated tumors and elucidate a treatment paradigm for VHL.http://www.sciencedirect.com/science/article/pii/S2211124712004329 |
| spellingShingle | Chunzhang Yang Kristin Huntoon Alexander Ksendzovsky Zhengping Zhuang Russell R. Lonser Proteostasis Modulators Prolong Missense VHL Protein Activity and Halt Tumor Progression Cell Reports |
| title | Proteostasis Modulators Prolong Missense VHL Protein Activity and Halt Tumor Progression |
| title_full | Proteostasis Modulators Prolong Missense VHL Protein Activity and Halt Tumor Progression |
| title_fullStr | Proteostasis Modulators Prolong Missense VHL Protein Activity and Halt Tumor Progression |
| title_full_unstemmed | Proteostasis Modulators Prolong Missense VHL Protein Activity and Halt Tumor Progression |
| title_short | Proteostasis Modulators Prolong Missense VHL Protein Activity and Halt Tumor Progression |
| title_sort | proteostasis modulators prolong missense vhl protein activity and halt tumor progression |
| url | http://www.sciencedirect.com/science/article/pii/S2211124712004329 |
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