title: An important von Hippel-Lindau tumor suppressor domain mediates Sp1-binding and self-association.
abstract: VHL is the causative gene for both von Hippel-Lindau (VHL) disease and sporadic clear-cell renal cancer. We showed earlier that VHL downregulates vascular endothelial growth factor transcription by directly binding and inhibiting the transcriptional activator Sp1. We have now mapped the VHL Sp1-binding domain to amino acids 96-122. The 96-122 domain is disproportionately affected by substitution mutations, which interfere with the VHL-Sp1 interaction. Deletion of the 96-122 domain prevents VHL effects on Sp1 DNA binding and on VHL target gene expression, indicating the domain contributes importantly to VHL tumor suppressor activity. Nevertheless, prevention of the VHL-Sp1 interaction only partially abrogates VHL's transcriptional repressor activity, supporting the existence of VHL transcriptional effectors in addition to Sp1. VHL also directly interacts with the Sp1 zinc fingers and self-associates via the 96-122 domain, which furthermore suggest the domain may bind other metalloproteins and contribute to VHL dominant-negative effects.
authors.affiliation: Renal and Hematology/Oncology Sections, Boston Medical Center and Boston University School of Medicine, Boston, MA 02118, USA. htcohen@bu.edu
authors.forename: H T
authors.initials: HT
authors.lastname: Cohen
authors.forename: M
authors.initials: M
authors.lastname: Zhou
authors.forename: A M
authors.initials: AM
authors.lastname: Welsh
authors.forename: S
authors.initials: S
authors.lastname: Zarghamee
authors.forename: H
authors.initials: H
authors.lastname: Scholz
authors.forename: D
authors.initials: D
authors.lastname: Mukhopadhyay
authors.forename: T
authors.initials: T
authors.lastname: Kishida
authors.forename: B
authors.initials: B
authors.lastname: Zbar
authors.forename: B
authors.initials: B
authors.lastname: Knebelmann
authors.forename: V P
authors.initials: VP
authors.lastname: Sukhatme
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D001665:Binding Sites; D002460:Cell Line; D019281:Dimerization; D015536:Down-Regulation; D016228:Endothelial Growth Factors / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008025:Ligases; D008222:Lymphokines / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D016335:Zinc Fingers
chemical_list: D016228:Endothelial Growth Factors; D008222:Lymphokines; D011506:Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D008025:Ligases; C497446:VHL protein, human