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

  1. Author:
    Cohen, H. T.
    Zhou, M.
    Welsh, A. M.
    Zarghamee, S.
    Scholz, H.
    Mukhopadhyay, D.
    Kishida, T.
    Zbar, B.
    Knebelmann, B.
    Sukhatme, V. P.

  2. Author Address

    Cohen HT Boston Univ, Med Ctr, Renal Sect E-428,88 E Newton St Boston, MA 02118 USA Boston Univ, Med Ctr, Renal Sect Boston, MA 02118 USA Boston Univ, Med Ctr, Hematol Oncol Sect Boston, MA 02118 USA Harvard Univ, Sch Med Boston, MA 02215 USA Beth Israel Deaconess Med Ctr, Div Renal Boston, MA 02215 USA NCI, Frederick Canc Res Ctr, Immunobiol Lab Frederick, MD 21702 USA
    1. Year: 1999
  2. Journal: Biochemical and Biophysical Research Communications
    1. 266
    2. 1
    3. Pages: 43-50
  4. Type of Article: Article
  1. 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 endo thelial growth factor transcription by directly binding and inhibiting the transcriptional activator Spl. We have now mapped the VHL Spl-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 Spl 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 Spl. VHL also directly interacts with the Spl 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. (C) 1999 Academic Press. [References: 32]

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