Genetic analysis of pathways regulated by the von Hippel-Lindau tumor suppressor in Caenorhabditis elegans.

Autor: Bishop T; The Henry Wellcome Building of Genomic Medicine, University of Oxford, Oxford, United Kingdom., Lau KW, Epstein AC, Kim SK, Jiang M, O'Rourke D, Pugh CW, Gleadle JM, Taylor MS, Hodgkin J, Ratcliffe PJ
Jazyk: angličtina
Zdroj: PLoS biology [PLoS Biol] 2004 Oct; Vol. 2 (10), pp. e289. Date of Electronic Publication: 2004 Sep 07.
DOI: 10.1371/journal.pbio.0020289
Abstrakt: 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.
Competing Interests: The authors have declared that no conflicts of interest exist.
Databáze: MEDLINE
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