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Regulation of transcription by heme with sperm reference to cell differentiation

血红素对精子转录的调节与细胞分化有关

基本信息

批准号：
14370048
负责人：
FUJITA Hiroyoshi
金额：
$ 7.62万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

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.

我们研究了Bach1，这是第一个发现的含有血红素的哺乳动物转录因子。我们先前的研究表明，该因子的一个亚基含有一摩尔的血红素，并且Bach1的DNA结合活性受到血红素饱和度的负调节。换言之，饱和血红素的Bach1失去了与mare位点的结合活性，从而为另一种转录因子如Nrf2、NFE2等提供了mare位点。然而，目前还没有很好地阐明Bach1/heme系统中处于负调控下的基因。在本研究中，我们检测了已知被其底物激活的家庭分解代谢的关键酶--母鸡加氧酶-1基因是否受Bach1/heme系统的控制。正如已经预期的那样，我们的数据清楚地表明，血红素加氧酶-1基因通过Bach1与MARE结合而受到负调控。因此，我们首次阐明了HERE介导的基因激活的确切机制，该基因对于代谢大量的血红素具有重要的生理意义，而血红素是一种生物有害的促氧化剂。除了血红素加氧酶-1基因外，我们还研究了β-珠蛋白基因的调控。众所周知，血红素和珠蛋白的合成是协调的，即没有血红素和珠蛋白的过度合成。调节等摩尔的血红素和珠蛋白的机制还不是很清楚。Bach1是控制血红蛋白形成的最可能的机制之一。事实上，我们的观察表明，珠蛋白基因中的Mear位点通过失去Bach1结合活性来控制血红素介导的上调。因此，在分化红系细胞的过程中，我们可以生物合成与家一样的珠蛋白。这样，我们就不会有危险的促氧化剂--血红素，即使是通过红系分化。