TY - JOUR
T1 - Inhibition of insulin-like growth factor-I-mediated cell signaling by the von Hippel-Lindau gene product in renal cancer
AU - Datta, Kaustubh
AU - Nambudripad, Raman
AU - Pal, Soumitro
AU - Zhou, Mi
AU - Cohen, Herbert T.
AU - Mukhopadhyay, Debabrata
PY - 2000/7/7
Y1 - 2000/7/7
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M909970199
DO - 10.1074/jbc.M909970199
M3 - Article
C2 - 10748176
AN - SCOPUS:0034617086
SN - 0021-9258
VL - 275
SP - 20700
EP - 20706
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 27
ER -