TY - JOUR
T1 - An important von Hippel-Lindau tumor suppressor domain mediates Sp1-binding and self-association
AU - Cohen, Herbert T.
AU - Zhou, Mi
AU - Welsh, Adam M.
AU - Zarghamee, Sharzad
AU - Scholz, Holger
AU - Mukhopadhyay, Debabrata
AU - Kishida, Takeshi
AU - Zbar, Berton
AU - Knebelmann, Bertrand
AU - Sukhatme, Vikas P.
N1 - Funding Information:
We thank J. Horowitz and W. Kaelin for generously providing reagents. This work was supported by NIH Grant DK02280 and a National Kidney Foundation Young Investigator Grant to H.T.C., NIH Grant F32 CA79133 to M.Z., a Fondation pour la Rechereche Medicale grant to B.K., and an NIH/NIDDK grant to V.P.S.
PY - 1999/12/9
Y1 - 1999/12/9
N2 - 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 effecters 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.
AB - 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 effecters 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.
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U2 - 10.1006/bbrc.1999.1767
DO - 10.1006/bbrc.1999.1767
M3 - Article
C2 - 10581162
AN - SCOPUS:17144445958
VL - 266
SP - 43
EP - 50
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 1
ER -