Inhibition of insulin-like growth factor-I-mediated cell signaling by the von Hippel-Lindau gene product in renal cancer.
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 von Hippel-Lindau (VHL) tumor suppresser gene. Moreover, molecular modeling and biochemical approaches have revealed that beta-domain of the VHL gene product by interacting directly with protein kinase Cdelta inhibits its association with IGF-IR for downstream signaling. We also demonstrated that RCC has IGF-I-mediated invasive activity where protein kinase Cdelta is an important downstream molecule, and this invasiveness can be blocked by wild type VHL. These experiments thus elucidate a novel tumor suppresser function of VHL with its unique kinase inhibitory domain.
Datta
K
K
Departments of Pathology and Molecular Computing Facility, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Nambudripad
R
R
Pal
S
S
Zhou
M
M
Cohen
H T
HT
Mukhopadhyay
D
D
D000595:Amino Acid Sequence; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D007680:Kidney Neoplasms / Q000378:metabolism*; D008025:Ligases; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011493:Protein Kinase C / Q000737:chemistry / Q000378:metabolism; D051745:Protein Kinase C-delta; D011506:Proteins / Q000737:chemistry / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000276:immunology / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D007527:Isoenzymes; D010446:Peptide Fragments; D011506:Proteins; D025521:Tumor Suppressor Proteins; D007334:Insulin-Like Growth Factor I; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D017526:Receptor, IGF Type 1; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D008025:Ligases; C497446:VHL protein, human