|Budget Amount *help
¥3,200,000 (Direct Cost : ¥3,200,000)
Fiscal Year 1998 : ¥800,000 (Direct Cost : ¥800,000)
Fiscal Year 1997 : ¥2,400,000 (Direct Cost : ¥2,400,000)
Heme oxygenase is an essential enzyme in heme catabolism that cleaves heme to release carbon monoxide, iron and biliverdin. There are at least two types of heme oxygenase isozymes, inducible heme oxygenase-1 and constitutively expressed heme oxygenase-2. We have found that expression heme oxygenase-l is induced by NO donors, such as sodium nitroprusside, in variouskinds of cultured cells including human glioblastoma cells (T98G and A 172), human cervical cancer cells (HeLa), melanoma cells (MeWo) and colonic carcinoma cells (DLD)- 1). Transient transfection assays using DLD-1 cells revealed that heme oxygenase-1 induction by sodium nitroprusside was mediated by cadmium-responsive element and AP-1, which are located in the promoter region of human heme oxygenase-1 gene (about -4.0 kb). In addition, we showed that a(GT)n repeat in the human heme oxygenase-1 gene promotor region (about -200 b) is highly polymorphic. On the other hand, expression of heme oxygenase-1 mRNA was considerably suppressed by interferon-gamma in T98G cells, suggesting the presence of a regulatory system for heme oxygenase-l overexpression in the brain.
Adrenomedullin is a vasodilator peptide isolated from pheochromocytoma. Although adrenomedullin was initially reported to be absent in the brain, we showed that adrenomedullinand its mRNA were highly expressed in the human brain and pituitary. Adrenomedullin is produced by various kinds of tumors including glioblastoma, choroid plexus carcinoma and colonic carcinoma, suggesting that adrenomedullin is related to the growth and proliferation of tumor cells. Heme oxygenase-1 is known to be induced by hypoxia. We showed that adrenomedullin was also induced by hypoxia. This induction may be a defense reaction agaist hypoxia, because adrenomedullin has vasodilator and bronchodilator actions.