Activation of insulin-like growth factor II signaling by mutant type p53: physiological implications for potentiation of IGF-II signaling by p53 mutant 249
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- Activation of insulin-like growth factor II signaling by mutant type p53: physiological implications for potentiation of IGF-II signaling by p53 mutant 249
- Young Ik Lee; Yoo Jung Han; Soo Young Lee; Yoon Ik Lee; Sook Kyung Park; Y J Park; H B Moon; J H Shin; J H Lee
- Bibliographic Citation
- Molecular and Cellular Endocrinology, vol. 203, no. 1, pp. 51-63
- Publication Year
- The aim of the present study was to investigate the intracellular mediators of the third base mutant of codon 249 in p53 gene (p53mt249) mutation that potentiate IGF-II dependent IGF-I receptor (IGF-IR) signaling. p53mt249 enhanced IGF-II dependent IGF-IR signaling in p53 negative Hep3B hepatoma cells which were specifically prevented by IGF-IR antibody, αIR3 and lovastin. p53mt249 increased the number of IGF-II binding sites with no change in the affinity of IGF-IR. Enhanced levels of IGF-IR expression and transcription were identified in p53mt249 transfected Hep3B cells. Pre-transfection of cultured hepatoma cells with p53mt249 resulted in a three to fourfold increase in IGF-IR phosphorylation and downstream mediator IRS-I phosphorylation but, enhanced more than 15-fold after IGF-II treatment, which coincides well with the cell growth and thymidine uptake results. Our results showed that p53mt249 modulate IGF-II dependent IGF-IR signaling by upregulating IGF-IR and potentiating IGF-IRs where IGF-IRs became more sensitive on treatment with IGF-II. We concluded that p53mt249 stimulates IGF-II dependent IGF-IR signaling by upregulating the expression of both ligand (IGF-II) (Oncogene 19 (2000) 3717) and receptor (IGF-IR) through an autocrine and/or paracrine loop and we outline the physiological significance of potentiation of IGF-IR by p53 mutation in the development of hepatocellular carcinoma (HCC).
- α-IR3; aflatoxin B1; AS-ODS; hepatocellular carcinoma; IGF-II/M6P-R; IGF-IR; IRS-1; P53mt249; RT-PCR; tyrosine phosphorylation
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