An important von Hippel-Lindau tumor suppressor domain mediates Sp1-binding and self-association.

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.

Cohen HT ，Zhou M ，Welsh AM ，Zarghamee S ，Scholz H ，Mukhopadhyay D ，Kishida T ，Zbar B ，Knebelmann B ，Sukhatme VP ... -  《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》

The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity.

Mukhopadhyay D ，Knebelmann B ，Cohen HT ，Ananth S ，Sukhatme VP ... -  《-》

Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel-Lindau tumor suppressor protein.

Siemeister G ，Weindel K ，Mohrs K ，Barleon B ，Martiny-Baron G ，Marmé D ... -  《CANCER RESEARCH》

Overproduction of vascular endothelial growth factor related to von Hippel-Lindau tumor suppressor gene mutations and hypoxia-inducible factor-1 alpha expression in renal cell carcinomas.

Na X ，Wu G ，Ryan CK ，Schoen SR ，di'Santagnese PA ，Messing EM ... -  《JOURNAL OF UROLOGY》

Activation of Sp1-mediated vascular permeability factor/vascular endothelial growth factor transcription requires specific interaction with protein kinase C zeta.

Pal S ，Claffey KP ，Cohen HT ，Mukhopadhyay D ... -  《JOURNAL OF BIOLOGICAL CHEMISTRY》