Activation of insulin-like growth factor II signaling by mutant type p53: physiological implications for potentiation of IGF-II signaling by p53 mutant 249.
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).
Lee
Young Ik
YI
Liver Cell Signal Transduction Lab., Korea Research Institute of Bioscience and Biotechnology, Taejon 305-606, Republic of Korea. yilee@mail.kribb.re.kr
Han
Yoo Jung
YJ
Lee
Soo Young
SY
Lee
Yoon Ik
YI
Park
Sook Kyung
SK
Park
Youn Jung
YJ
Moon
Hyung Bae
HB
Shin
Jeh Hoon
JH
Lee
Je Ho
JH
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*
D016159:Tumor Suppressor Protein p53; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1