Genetic analysis of pathways regulated by the von Hippel-Lindau tumor suppressor in Caenorhabditis elegans.
The von Hippel-Lindau (VHL) tumor suppressor functions as a ubiquitin ligase that mediates proteolytic inactivation of hydroxylated alpha subunits of hypoxia-inducible factor (HIF). Although studies of VHL-defective renal carcinoma cells suggest the existence of other VHL tumor suppressor pathways,...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2004-10-01
|
| Series: | PLoS Biology |
| Online Access: | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.0020289&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823856945644175360 |
|---|---|
| author | Tammie Bishop Kah Weng Lau Andrew C R Epstein Stuart K Kim Min Jiang Delia O'Rourke Christopher W Pugh Jonathan M Gleadle Martin S Taylor Jonathan Hodgkin Peter J Ratcliffe |
| author_facet | Tammie Bishop Kah Weng Lau Andrew C R Epstein Stuart K Kim Min Jiang Delia O'Rourke Christopher W Pugh Jonathan M Gleadle Martin S Taylor Jonathan Hodgkin Peter J Ratcliffe |
| author_sort | Tammie Bishop |
| collection | DOAJ |
| description | The von Hippel-Lindau (VHL) tumor suppressor functions as a ubiquitin ligase that mediates proteolytic inactivation of hydroxylated alpha subunits of hypoxia-inducible factor (HIF). Although studies of VHL-defective renal carcinoma cells suggest the existence of other VHL tumor suppressor pathways, dysregulation of the HIF transcriptional cascade has extensive effects that make it difficult to distinguish whether, and to what extent, observed abnormalities in these cells represent effects on pathways that are distinct from HIF. Here, we report on a genetic analysis of HIF-dependent and -independent effects of VHL inactivation by studying gene expression patterns in Caenorhabditis elegans. We show tight conservation of the HIF-1/VHL-1/EGL-9 hydroxylase pathway. However, persisting differential gene expression in hif-1 versus hif-1; vhl-1 double mutant worms clearly distinguished HIF-1-independent effects of VHL-1 inactivation. Genomic clustering, predicted functional similarities, and a common pattern of dysregulation in both vhl-1 worms and a set of mutants (dpy-18, let-268, gon-1, mig-17, and unc-6), with different defects in extracellular matrix formation, suggest that dysregulation of these genes reflects a discrete HIF-1-independent function of VHL-1 that is connected with extracellular matrix function. |
| format | Article |
| id | doaj-art-eb68e705940c425ca62a683545f28f74 |
| institution | Kabale University |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2004-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj-art-eb68e705940c425ca62a683545f28f742025-02-12T05:30:23ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852004-10-01210e28910.1371/journal.pbio.0020289Genetic analysis of pathways regulated by the von Hippel-Lindau tumor suppressor in Caenorhabditis elegans.Tammie BishopKah Weng LauAndrew C R EpsteinStuart K KimMin JiangDelia O'RourkeChristopher W PughJonathan M GleadleMartin S TaylorJonathan HodgkinPeter J RatcliffeThe von Hippel-Lindau (VHL) tumor suppressor functions as a ubiquitin ligase that mediates proteolytic inactivation of hydroxylated alpha subunits of hypoxia-inducible factor (HIF). Although studies of VHL-defective renal carcinoma cells suggest the existence of other VHL tumor suppressor pathways, dysregulation of the HIF transcriptional cascade has extensive effects that make it difficult to distinguish whether, and to what extent, observed abnormalities in these cells represent effects on pathways that are distinct from HIF. Here, we report on a genetic analysis of HIF-dependent and -independent effects of VHL inactivation by studying gene expression patterns in Caenorhabditis elegans. We show tight conservation of the HIF-1/VHL-1/EGL-9 hydroxylase pathway. However, persisting differential gene expression in hif-1 versus hif-1; vhl-1 double mutant worms clearly distinguished HIF-1-independent effects of VHL-1 inactivation. Genomic clustering, predicted functional similarities, and a common pattern of dysregulation in both vhl-1 worms and a set of mutants (dpy-18, let-268, gon-1, mig-17, and unc-6), with different defects in extracellular matrix formation, suggest that dysregulation of these genes reflects a discrete HIF-1-independent function of VHL-1 that is connected with extracellular matrix function.https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.0020289&type=printable |
| spellingShingle | Tammie Bishop Kah Weng Lau Andrew C R Epstein Stuart K Kim Min Jiang Delia O'Rourke Christopher W Pugh Jonathan M Gleadle Martin S Taylor Jonathan Hodgkin Peter J Ratcliffe Genetic analysis of pathways regulated by the von Hippel-Lindau tumor suppressor in Caenorhabditis elegans. PLoS Biology |
| title | Genetic analysis of pathways regulated by the von Hippel-Lindau tumor suppressor in Caenorhabditis elegans. |
| title_full | Genetic analysis of pathways regulated by the von Hippel-Lindau tumor suppressor in Caenorhabditis elegans. |
| title_fullStr | Genetic analysis of pathways regulated by the von Hippel-Lindau tumor suppressor in Caenorhabditis elegans. |
| title_full_unstemmed | Genetic analysis of pathways regulated by the von Hippel-Lindau tumor suppressor in Caenorhabditis elegans. |
| title_short | Genetic analysis of pathways regulated by the von Hippel-Lindau tumor suppressor in Caenorhabditis elegans. |
| title_sort | genetic analysis of pathways regulated by the von hippel lindau tumor suppressor in caenorhabditis elegans |
| url | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.0020289&type=printable |
| work_keys_str_mv | AT tammiebishop geneticanalysisofpathwaysregulatedbythevonhippellindautumorsuppressorincaenorhabditiselegans AT kahwenglau geneticanalysisofpathwaysregulatedbythevonhippellindautumorsuppressorincaenorhabditiselegans AT andrewcrepstein geneticanalysisofpathwaysregulatedbythevonhippellindautumorsuppressorincaenorhabditiselegans AT stuartkkim geneticanalysisofpathwaysregulatedbythevonhippellindautumorsuppressorincaenorhabditiselegans AT minjiang geneticanalysisofpathwaysregulatedbythevonhippellindautumorsuppressorincaenorhabditiselegans AT deliaorourke geneticanalysisofpathwaysregulatedbythevonhippellindautumorsuppressorincaenorhabditiselegans AT christopherwpugh geneticanalysisofpathwaysregulatedbythevonhippellindautumorsuppressorincaenorhabditiselegans AT jonathanmgleadle geneticanalysisofpathwaysregulatedbythevonhippellindautumorsuppressorincaenorhabditiselegans AT martinstaylor geneticanalysisofpathwaysregulatedbythevonhippellindautumorsuppressorincaenorhabditiselegans AT jonathanhodgkin geneticanalysisofpathwaysregulatedbythevonhippellindautumorsuppressorincaenorhabditiselegans AT peterjratcliffe geneticanalysisofpathwaysregulatedbythevonhippellindautumorsuppressorincaenorhabditiselegans |