Inhibition of insulin-like growth factor-I-mediated cell signaling by the von Hippel-Lindau gene product in renal cancer

Kaustubh Datta, Raman Nambudripad, Soumitro Pal, Mi Zhou, Herbert T. Cohen, Debabrata Mukhopadhyay

Research output: Contribution to journalArticle

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Abstract

Insulin-like growth factor-I (IGF-I)-mediated signaling is thought to be involved in the regulation of multiple cellular functions in different tumors including renal cell carcinoma (RCC). Blocking IGF-I signaling by any of the several strategies abolishes or delays the progression of a variety of tumors in animal models. Herein, we demonstrate that in RCC cell lines, IGF-I- mediated signaling is found to be inhibited in the presence of wild type yon Hippel-Lindau (VHL) tumor suppresser gene. Moreover, molecular modeling and biochemical approaches have revealed that β-domain of the VHL gene product by interacting directly with protein kinase Cδ inhibits its association with IGF-IR for downstream signaling. We also demonstrated that RCC has IGF-I- mediated invasive activity where protein kinase Cδ is an important downstream molecule, and this invasiveness can be blocked by wild type VEIL. These experiments thus elucidate a novel tumor suppresser function of VHL with its unique kinase inhibitory domain.

Original languageEnglish (US)
Pages (from-to)20700-20706
Number of pages7
JournalJournal of Biological Chemistry
Volume275
Issue number27
DOIs
StatePublished - Jul 7 2000

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Cell signaling
Kidney Neoplasms
Insulin-Like Growth Factor I
Tumors
Genes
Renal Cell Carcinoma
Protein Kinase C
Neoplasms
Cells
Molecular modeling
Animals
Phosphotransferases
Animal Models
Cell Line
Molecules
Experiments

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Inhibition of insulin-like growth factor-I-mediated cell signaling by the von Hippel-Lindau gene product in renal cancer. / Datta, Kaustubh; Nambudripad, Raman; Pal, Soumitro; Zhou, Mi; Cohen, Herbert T.; Mukhopadhyay, Debabrata.

In: Journal of Biological Chemistry, Vol. 275, No. 27, 07.07.2000, p. 20700-20706.

Research output: Contribution to journalArticle

Datta, Kaustubh ; Nambudripad, Raman ; Pal, Soumitro ; Zhou, Mi ; Cohen, Herbert T. ; Mukhopadhyay, Debabrata. / Inhibition of insulin-like growth factor-I-mediated cell signaling by the von Hippel-Lindau gene product in renal cancer. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 27. pp. 20700-20706.
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