KITAMURA Hiroshi Yokohama City University, School of Medicine, Professor, 医学部, 教授 (20094302)
KAGEYAMA Ryoichiro Kyoto University, Virus Institute, Professor, ウイルス研究所, 教授 (80224369)
YAZAWA Takuya Yokohama City University, School of Medicine, Assistant Professor, 医学部, 講師 (50251054)
|Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2001: ¥2,000,000 (Direct Cost: ¥2,000,000)
The Notch signaling pathway plays an important role in determining cell fate of various cell system, and is considered to function in cell fate determination of the lung epithelia and lung carcinoma. And, the pathway works through regulating the network of proneural basic helix-loop helix factors.
We did some experimental studies to clarify the significance of the Notch pathway in the lung, and gained the following results. 1) Immunohistochemical and Northern blot studies revealed that pulmonary neuroendocrine cells of the mouse (PNEC) showed positive staining for Mash1, Hes1(Cytoplasmic stain), Delta-like1(DII-1), but non-PNEC showed positive staining for Hes1 (nuclear and cytoplasmic stain), Notch-3, Jagged1-2. Expression of DII-1 is not detected in the lungs of Mash1 gene null mice, and expression of Notch1 is decreased in the lung of Hes1 gene null mice. 2) In human lung cancer cell lines, small cell carcinoma cells expressed hASH1, Hes1, DII-1, Jag1, and Jag2, but non-small cell carcinoma cells expressed Hes1, Notch1-Notch3, and Jag1. 3) Transfection of Notch1 gene and intracytoplasmic domain of Notch1 gene suppressed cell proliferation rate, abolished neuroendocrine differentiation and induced epithelial morphology with enhanced cell adhesiveness.
Thus, theses studies support that the Notch signaling pathway and the basic helix-loop-helix factor network could be important in cell differentiation regulation in human lung diseases.