title: Activation of insulin-like growth factor II signaling by mutant type p53: physiological implications for potentiation of IGF-II signaling by p53 mutant 249.
abstract: 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, alpha IR3 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) 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).
authors.affiliation: Liver Cell Signal Transduction Lab., Korea Research Institute of Bioscience and Biotechnology, Taejon 305-606, Republic of Korea. yilee@mail.kribb.re.kr
authors.forename: Young Ik
authors.initials: YI
authors.lastname: Lee
authors.forename: Yoo Jung
authors.initials: YJ
authors.lastname: Han
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Yoon Ik
authors.initials: YI
authors.lastname: Lee
authors.forename: Sook Kyung
authors.initials: SK
authors.lastname: Park
authors.forename: Youn Jung
authors.initials: YJ
authors.lastname: Park
authors.forename: Hyung Bae
authors.initials: HB
authors.lastname: Moon
authors.forename: Jeh Hoon
authors.initials: JH
authors.lastname: Shin
authors.forename: Je Ho
authors.initials: JH
authors.lastname: Lee
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000473:pathology; D002450:Cell Communication; D002455:Cell Division; D045744:Cell Line, Tumor; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
chemical_list: D016159:Tumor Suppressor Protein p53; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1