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

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.

• Authors: Yanlai Lai, Meihua Song, Kevin Hakala, Susan T Weintraub, Yuzuru Shiio
• Journal: Archives of biochemistry and biophysics (Arch Biochem Biophys) Vol. 518 Issue 2 Pg. 103-10 (Feb 15 2012) ISSN: 1096-0384 [Electronic] United States
• PMID: 22234250 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• 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

Topics

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