The interaction of the von Hippel-Lindau tumor suppressor and heterochromatin protein 1

Arch Biochem Biophys. 2012 Feb 15;518(2):103-10. doi: 10.1016/j.abb.2011.12.023. Epub 2012 Jan 3.

Abstract

Inactivation of the von Hippel-Lindau (VHL) tumor suppressor is associated with renal carcinoma, hemangioblastoma and pheochromocytoma. The VHL protein is a component of a ubiquitin ligase complex that ubiquitinates and degrades hypoxia inducible factor-α (HIF-α). Degradation of HIF-α by VHL is proposed to suppress tumorigenesis and tumor angiogenesis. Several lines of evidence also suggest important roles for HIF-independent VHL functions in tumor suppression and other biological processes. Using GST-VHL pull-down experiment and mass spectrometry, we detected an interaction between VHL and heterochromatin protein 1 (HP1). We identified a conserved HP1-binding motif (PXVXL) in the β domain of VHL, which is disrupted in a renal carcinoma-associated P81S mutant. We show that the VHL P81S mutant displays reduced binding to HP1, yet retains the ability to interact with elongin B, elongin C, and cullin 2 and is fully capable of degrading HIF-α. We also demonstrate that HP1 increases the chromatin association of VHL. These results suggest a role for the VHL-HP1 interaction in VHL chromatin targeting.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Substitution
  • Animals
  • Cell Line
  • Chromatin / genetics
  • Chromatin / metabolism*
  • Chromobox Protein Homolog 5
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Cullin Proteins / genetics
  • Cullin Proteins / metabolism
  • Elongin
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism*
  • Mice
  • Mutation, Missense
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism
  • Proteolysis*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Ubiquitination / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism*

Substances

  • CUL2 protein, human
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Cullin Proteins
  • ELOB protein, human
  • ELOC protein, human
  • Elob protein, mouse
  • Eloc protein, mouse
  • Elongin
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Transcription Factors
  • Chromobox Protein Homolog 5
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human