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

Abstract

The von Hippel-Lindau tumour suppressor gene (VHL) targets hypoxia inducible factor (HIF)-α subunits for ubiquitin dependent proteolysis. To better understand the role of this and other putative pathways of gene regulation in VHL function we subjected mRNA from VHL defective renal carcinoma cells and transfectants re-expressing a wild type VHL allele to differential expression profiling, and analysed VHL target genes for oxygen regulated expression. 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 transcription, VHL has other influences on patterns of gene expression. Genes newly defined 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-related protein 1, MIC2/CD99, and transglutaminase 2. These genes have a variety of functions relevant to tumour biology. However, not all are connected with the promotion of tumour growth, some being pro-apoptotic or growth inhibitory. We postulate that co-ordinate regulation as part of the HIF pathway may explain this paradox, and that evolution of anti-apoptotic pathways may be required for tumour growth under VHL-dysregulation. Our results indicate 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.

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Abbreviations

VHL:

von Hippel-Lindau

HIF-1:

hypoxia inducible factor-1

RCC:

renal cell carcinoma

RPA:

ribonuclease protection assay

GEM:

gene expression microarray

LC:

U6 small nuclear RNA

GLUT-1:

glucose transporter 1

VEGF:

vascular endothelial growth factor

EDN1:

endothelin-1

DEC1:

differentiated embryo chrondocyte 1

Stra13:

stimulated with retinoic acid 13

MIC2:

monoclonal, Imperial Cancer Research Fund 2

TGM2:

transglutaminase 2

LRP1:

low density lipoprotein receptor-related protein 1

COL5A1:

collagen type V, alpha 1

CCNG2:

cyclin G2

APA:

aminopeptidase A

VIM:

vimentin

SGNE1:

secretory granule neuroendocrine protein 1

SAT:

spermidine N1-acetyltransferase

KRTHB1:

keratin, hair, basic, 1

CTSC:

cathepsin C

K18:

keratin 18

EST:

expressed sequence tag

IF:

I factor

CHO:

Chinese hamster ovary

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Acknowledgements

This work was supported by the Wellcome Trust, the Medical Research Council, and the Imperial Cancer Research Fund.

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Wykoff, C., Pugh, C., Maxwell, P. et al. Identification of novel hypoxia dependent and independent target genes of the von Hippel-Lindau (VHL) tumour suppressor by mRNA differential expression profiling. Oncogene 19, 6297–6305 (2000). https://doi.org/10.1038/sj.onc.1204012

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