2005 Fiscal Year Final Research Report Summary
Analysis of IGF-I receptor transcriptional regulation by mutant p53 and its clinical implication
| Project/Area Number |
16591661
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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 |
Obstetrics and gynecology
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| Research Institution | Okayama University |
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Principal Investigator |
HONGO Atsushi Okayama University, Hospital, Research Associate, 医学部・歯学部附属病院, 助手 (10301293)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAMURA Keiichiro Okayama University, Hospital, Research Associate, 医学部・歯学部附属病院, 助手 (90359886)
KODAMA Junichi Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Associate Professor, 大学院医歯薬学総合研究科, 助教授 (90263582)
HIRAMATSU Yuji Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Professor, 大学院医歯薬学総合研究科, 教授 (80218817)
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| Project Period (FY) |
2004 – 2005
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| Keywords | mutant p53 / IGF-I receptor / transcriptional regulation / anchorage independent growth / tumor formation |
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| Research Abstract |
The role of wild type p53 on IGF-I receptor expression was studied in cervical cancer derived cell lines SiHa and HeLa S3 harboring HPV. Transient transfection of E6 into SiHa cells downregulated p53, and upregulated IGF-I receptor. In contrast, transient transfection of E2 into HeLa S3 cells upregulated p53, and downregulated IGF-I receptor. We could reconfirm these phenomena by establishing stable transformants of these genes. Luciferase assay driven by IGF-I receptor promoter revealed that these alternation of IGF-I receptor expression was based on transcriptional regulation. Alternation of IGF-I receptor expression within these stable transformants did effect on their anchorage-independent growth in soft agar, and tumorigenesity in nude mice.
Then, expression levels and their tyrosil phosphorylated status in human cervical specimens were evaluated by immunohistochemistry. IGF-I receptor expression levels were significantly promoted in CIN III lesions and more. Phosphorylated IGF-I receptor was observed in all CIN and invasive cancer specimens, and its promotion was related to the progression of the disease.
Then, transcriptional regulation on IGF-I receptor by mutant p53 was evaluated. We constructed expression vectors encoding wild type and various p53 mutants especially within hot spot mutation areas. Luciferase assay after transient transfection of these wild type and mutant p53 genes showed different transcriptional regulations of IGF-I receptor. Wild type as well as P72R and V143A mutants downregulated IGF-I receptor transcription, whereas other mutants T123A, R175H, R248Q, R273H had no effect.
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Research Products
(2 results)
