2007 Fiscal Year Final Research Report Summary
Physiological and pathological role of inositol phospholipids
| Project/Area Number |
18390094
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Kyushu University (2007)
Akita University (2006) |
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Principal Investigator |
SUZUKI Akira Kyushu University, Medical institute of Bioregulation, Professor (10311565)
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| Project Period (FY) |
2006 – 2007
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| Keywords | PTEN / PI3-kinase / Cancer suppressor gene / Lipid / Phosphatase / Bronchioalveolar epithelium / NKT cells / Urothelium |
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| Research Abstract |
In this study, we have analyzed the functions of PTEN mainly in bronchioalveolar epithelial cells, NKT cells, and urothelial epithelial cells as follows;
1 Ninety percent of bronchioalveolar epithelium-specific Pten mutant mice died of hypoxia soon after birth, and surviving mice developed spontaneous lung adenocarcinomas. Histological examinations of the lungs revealed hyperplasia of bronchioalveolar epithelial cells and myofibroblast precursors, and impaired production of surfactant proteins. Numbers of bronchioalveolar stem cells(BASCs), putative initiators of lung adenocarcinomas, were also increased. These results indicate that Pten is essential for both normal lung morphogenesis and the prevention of lung carcinogenesis, possibly because this tumor suppressor is required for BASC homeostasis.
2 A failure in the development of Va14iNKT cells occurs by Pten mutation in NKT cells. In addition, Pten-deficient Va14iNKT cells show reduced proliferation and cytokine secretion in response
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to αGalCer stimulation in vitro. In vivo, Va14iNKT cell-mediated protection against the metastasis of melanoma cells to the lung was impaired in the absence of Pten. Thus, the Pten/PI3K pathway is indispensable for the homeostasis and antitumor surveillance function of Va14iNKT cells.
3 All urothelium-specific null mutation of Pten in mice exhibited urothelial hyperplasia. With time, 10% of mutant mice spontaneously developed pedicellate papillary transitional cell carcinomas(TCC). In humans, more than half of primary bladder cancer patients exhibited decreased or absent expression of PTEN protein in either the cytoplasm or nucleus of tumor cells. Thus, PTEN deficiency may contribute to bladder cancer.
4 Furthermore, we reported that electrical signals control skin wound healing through phosphatidylinositol-3-OH kinase-gamma and PTEN; PTEN is a critical determinant of body size and glucose metabolism when targeting is driven by the rat insulin promoter; and control of cell polarity and motility by PI(3,4,5) P3 phosphatase is governed by SHIP rather than PTEN in neutrophils. Less
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