title: 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.affiliation: Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
authors.forename: Yanlai
authors.initials: Y
authors.lastname: Lai
authors.forename: Meihua
authors.initials: M
authors.lastname: Song
authors.forename: Kevin
authors.initials: K
authors.lastname: Hakala
authors.forename: Susan T
authors.initials: ST
authors.lastname: Weintraub
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Shiio
mesh_terms: D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D000075065:Elongin; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D020125:Mutation, Missense; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C105153:CUL2 protein, human; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D044842:Cullin Proteins; C000616396:ELOB protein, human; C000616395:ELOC protein, human; C000616401:Elob protein, mouse; C000616411:Eloc protein, mouse; D000075065:Elongin; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D000090266:Chromobox Protein Homolog 5; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human