| Project/Area Number |
10670749
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
HOSOI Hajime Kyoto Prefectural University of Medicine, Pediatrics, Assistant Professor, 医学部, 助手 (20238744)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1999: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1998: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Keywords | neuroblastoma / N-myc / retinoic acid / differentiation / IGF-I / MAPK / 神経芽細胞腫 / mycN / mxi1 / max / レチノイン酸誘導体 / 細胞周期 |
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| Research Abstract |
Insulin-like growth factor I (IGF-I) stimulates proliferation, survival and differentiation in many cell types, including the pediatric neuroblastomas. The effect is mediated via the type I IGF-I receptor (IGF-IR), which is essential for growth in these cells. Several lines of evidence indicated that IGF-IR function may be particular important in the pathogenesis of the neuroblastoma. Amplification of the N-myc oncogene or overexpression of N-Myc oncoprotein have been reported to be associated with resistance to therapy and poor prognosis of neuroblastomas. It was therefore of interest to analyze whether IGF-I signaling regulated expression on N-myc in KP-N-RT human neuroblastoma cells as an experimental model that has amplified N-myc. We found that IGF-I induces N-myc mRNA and protein in the KP-N-RT with the maximum of 4 and 6 times more than the basal level at 2 and 3 hrs after the stimulation, respectively. These effects of IGF-I were blocked by a neutralizing antibody against IGF-IR (α-IR3). Exogenous IGF-I induced phosphorylation of extracellular signal-regulated kinases p42/44 (Erk1 and Erk2), with a maximal level 30 min after the stimulation. The MEK1 inhibitor PD98059 reduced IGF-I-mediated p42/44 tyrosine phosphorylation, and produced a parallel reduction of IFG-I-stimulated N-Myc induction. Furthermore, both α-IR3 and PD98059 inhibited G1-S cell cycle progression stimulated by IGF-I. Our results demonstrate that IGF-I induces N-Myc in the KP-N-RT neuroblastoma cell line at the RNA level and establishes a clear correlation between N-Myc induction and activation of p42/44 MAPK signaling.
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