Study for physiological function of metastin/kisspeptin with special reference to reproduction.

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We previously found that metastin/kisspeptin is produced in anteroventral periventricular nucleus(AVPV) and arcuate nucleus(Arc.) in the hypothalamus. It is also revealed that metastin gene (kiss-1) expression in AVPV is positively and Arc is negatively regulated by estrogen and may be involved in ovulation and gonadal development through the surge or pulse mode release of GnRH/LH. In this study we found a clock gene which regulates metastin gene expression. The clock gene (Dbp) shows not only additive effects with E2 and it's nuclear receptor ERa on the expression of metastin, but correlation of spatio-temporal expression pattern between Dbp and metastin. These results strongly suggest Dbp is key regulator, which set a time of LH surge.In this study we also performed immunocytochemical study for metastin and GnRH neurons and found that metastin and GnRH nerve fibers closely contacted at median eminence, which strongly suggest that metastin may regulate GnRH neurons in median eminence. On the other hand, metastin is found as a peptide which suppresses metastasis of cancer cells however, the effect of metastin on metastasis is not well studied. In this study we found that metastin activates ERK1/2 gene in many kind of cancer cells. We also found that metastin has no effect on the cancer cell proliferation and apoptosis however, it inhibited migration of a mammary carcinoma and a lung carcinoma cells.