|Budget Amount *help
¥11,900,000 (Direct Cost: ¥11,900,000)
Fiscal Year 2004: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 2003: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2002: ¥6,400,000 (Direct Cost: ¥6,400,000)
We have investigated Bach1, the first found mammalian transcriptional factor that contains heme. Our previous investigations reveals that the factor contains one mole of heme per one subunit, and that the DNA binding activity of Bach1 is negatively regulated by heme saturation. In other words, heme saturated Bach1 lose its binding activity against MARE site resulting in an available MARE site for another transcriptional factors such as Nrf2, NFE2 and so on.
It has been, however, not yet well elucidated the genes that are under the negative control in Bach1/heme system. In the present study, we have examined if hens oxygenase-1 gene, the key enzyme of home catabolism, which is well known to activated by its substrate, is under the control of Bach1/heme system or not. As was already expected, our data is clearly indicated that heme oxygenase-1 gene was negatively regulated through Bach1 binding to MARE site. Hereby, we elucidated for the first time the precise mechanism of here mediated activation of gene that is physiologically important to metabolize a huge amount of heme, a biologically harmful pro-oxidant.
In addition to heme oxygenase-1 gene, we have examined the regulation of beta-globin gene. It is well known that heme and globin syntheses for hemoglobin are coordinated ; i.e., there are no exceeded syntheses for heme and globin. The mechanism to regulate equal mole of heme and globin has not been well understood. Bach1 is one of the most possible mechanisms to control hemoglobin formation. Indeed, our observations demonstrated that MEAR site in globin gene ruled heme mediated upregulation via the loss of Bach1 binding activity. Thus, we can biosynthesize globin protein just equal to home in differentiating erythroid cells. In this way, we are free form dangerous pro-oxidant, heme, even through erythroid differentiation.