Inhibition of HIF2α Is Sufficient to Suppress pVHL-Defective Tumor Growth

Abstract

Biallelic inactivation of the von Hippel-Lindau tumor suppressor gene (VHL) is linked to the development of hereditary (VHL-associated) and sporadic clear-cell renal carcinomas as well as other abnormalities. The VHL gene product, pVHL, is part of an E3 ubiquitin ligase complex that targets the alpha subunits of the heterodimeric transcription factor HIF (hypoxia-inducible factor) for degradation in the presence of oxygen. Here we report that a HIF2alpha variant lacking both of its two prolyl hydroxylation/pVHL-binding sites prevents tumor inhibition by pVHL in a DNA-binding dependent manner. Conversely, downregulation of HIF2alpha with short hairpin RNAs is sufficient to suppress tumor formation by pVHL-defective renal carcinoma cells. These results establish that tumor suppression by pVHL is linked to regulation of HIF target genes.

Cited by papers we hold 10

• Von Hippel–Lindau disease: insights into oxygen sensing, protein degradation, and cancer · 2022
  No notice
• HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice · 2020
  No notice
• A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis · 2019
  No notice
• Molecular Mechanisms and Signaling Pathways Involved in Sertoli Cell Proliferation · 2019
  No notice
• Tumor hypoxia induces nuclear paraspeckle formation through HIF-2α dependent transcriptional activation of NEAT1 leading to cancer cell survival · 2014
  Corrected
• Hypoxia inducible factors in cancer stem cells · 2010
  No notice
• Differences in regulation of tight junctions and cell morphology between VHL mutations from disease subtypes · 2009
  Not checked
• Gene Expression Programs in Response to Hypoxia: Cell Type Specificity and Prognostic Significance in Human Cancers · 2006
  No notice
• A HIF1α Regulatory Loop Links Hypoxia and Mitochondrial Signals in Pheochromocytomas · 2005
  No notice
• Genetic Analysis of Pathways Regulated by the von Hippel-Lindau Tumor Suppressor in Caenorhabditis elegans · 2004
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.