Martin F, van Deursen J M, Shivdasani R A, Jackson C W, Troutman A G, Ney P A
Department of Biochemistry, Saint Jude Children's Research Hospital, Memphis, TN, USA.
Blood. 1998 May 1;91(9):3459-66.
NF-E2 binding sites, located in distant regulatory sequences, may be important for high level alpha- and beta-globin gene expression. Surprisingly, targeted disruption of each subunit of NF-E2 has either little or no effect on erythroid maturation in mice. For p18 NF-E2, this lack of effect is due, at least in part, to the presence of redundant proteins. For p45 NF-E2, one possibility is that NF-E2-related factors, Nrf-1 or Nrf-2, activate globin gene expression in the absence of NF-E2. To test this hypothesis for Nrf-2, we disrupted the Nrf-2 gene by homologous recombination. Nrf-2-deficient mice had no detectable hematopoietic defect. In addition, no evidence was found for reciprocal upregulation of NF-E2 or Nrf-2 protein in fetal liver cells deficient for either factor. Fetal liver cells deficient for both NF-E2 and Nrf-2 expressed normal levels of alpha- and beta-globin. Mature mice with combined deficiency of NF-E2 and Nrf-2 did not exhibit a defect in erythroid maturation beyond that seen with loss of NF-E2 alone. Thus, the presence of a mild erythroid defect in NF-E2-deficient mice is not the result of compensation by Nrf-2.
位于远距离调控序列中的NF-E2结合位点，可能对α和β珠蛋白基因的高水平表达很重要。令人惊讶的是，对NF-E2每个亚基进行靶向破坏对小鼠的红细胞成熟几乎没有影响或没有影响。对于p18 NF-E2，这种缺乏影响至少部分是由于存在冗余蛋白。对于p45 NF-E2，一种可能性是NF-E2相关因子Nrf-1或Nrf-2在没有NF-E2的情况下激活珠蛋白基因表达。为了验证Nrf-2的这一假设，我们通过同源重组破坏了Nrf-2基因。Nrf-2缺陷小鼠没有可检测到的造血缺陷。此外，在缺乏任一因子的胎肝细胞中，未发现NF-E2或Nrf-2蛋白相互上调的证据。同时缺乏NF-E2和Nrf-2的胎肝细胞表达正常水平的α和β珠蛋白。NF-E2和Nrf-2联合缺陷的成熟小鼠，除了单独缺失NF-E2时出现的红细胞成熟缺陷外，没有表现出其他缺陷。因此，NF-E2缺陷小鼠中轻度红细胞缺陷的存在不是Nrf-2补偿的结果。
