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, 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.
Bishop
Tammie
T
The Henry Wellcome Building of Genomic Medicine, University of Oxford, Oxford, United Kingdom.
Lau
Kah Weng
KW
Epstein
Andrew C R
AC
Kim
Stuart K
SK
Jiang
Min
M
O'Rourke
Delia
D
Pugh
Christopher W
CW
Gleadle
Jonathan M
JM
Taylor
Martin S
MS
Hodgkin
Jonathan
J
Ratcliffe
Peter J
PJ
D000818:Animals; D001483:Base Sequence; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002874:Chromosome Mapping; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D015536:Down-Regulation; D019143:Evolution, Molecular; D005109:Extracellular Matrix / Q000378:metabolism; D005786:Gene Expression Regulation; D016678:Genome; D006801:Humans; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D012260:Ribonucleases / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; C403074:Egl-9 protein, C elegans; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D012260:Ribonucleases