Identification of novel hypoxia dependent and independent target genes of the von Hippel-Lindau (VHL) tumour suppressor by mRNA differential expression profiling

The von Hippel-Lindau tumour suppressor gene (VHL) targets hypoxia inducibl e factor (HIF)-alpha subunits for ubiquitin dependent proteolysis, To bette r understand the role of this and other putative pathways of gene regulatio n in VHL function we subjected mRNA from VHL defective renal carcinoma cell s and transfectants re-expressing a wild type VHL allele to differential ex pression profiling, and analysed VHL target genes for oxygen regulated expr ession, Among a group of newly identified VHL target genes the majority but not all were regulated by oxygen, indicating that whilst dysregulation of the HIF system makes a dominant contribution to alterations in transcriptio n, VHL has other influences on patterns of gene expression. Genes newly def ined as targets of the VHL/hypoxia pathway (conditionally downregulated by VHL in normoxic cells) include aminopeptidase A, collagen type V, alpha 1, cyclin G2, DEC1/Stra13, endothelin 1, low density lipoprotein receptor-rela ted protein 1, MIC2/CD99, and transglutaminase 2. These genes have a variet y of functions relevant to tumour biology. However, not all are connected w ith the promotion of tumour growth, some being pro-apoptotic or growth inhi bitory. We postulate that co-ordinate regulation as part of the HIF pathway may explain this paradox, and that evolution of anti; apoptotic pathways m ay be required for tumour growth under VHL-dysregulation, Our results indic ate that it will be necessary to consider the effects of abnormal activity in integral regulatory pathways, as well as the effects of individual genes to understand the role of abnormal patterns of gene expression in cancer.