Yan Bo, Raben Nina, Plotz Paul H
Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Building 10, Room 9N244, 9000 Rockville Pike, Bethesda, Maryland 20892-1820, USA.
Biochem Biophys Res Commun. 2002 Mar 1;291(3):582-7. doi: 10.1006/bbrc.2002.6483.
Hes-1, the mammalian homologue 1 of Drosophila hairy and Enhancer of split proteins, belongs to a family of basic helix-loop-helix proteins that are essential to neurogenesis, myogenesis, hematopoiesis, and sex determination. Hes-1 is a transcriptional repressor for a number of known genes including the human acid alpha-glucosidase (GAA) gene as we have previously shown in Hep G2 cells. The human GAA gene encodes the enzyme for glycogen breakdown in lysosomes, deficiency of which results in Glycogen Storage Disease type II (Pompe syndrome). Using constructs containing the DNA element that demonstrates repressive activity in Hep G2 cells and conditions in which the same transcription factors, Hes-1 and YY1, bind, we have shown that this element functions as an enhancer in human fibroblasts. Site-directed mutagenesis and overexpression of Hes-1 showed that Hes-1 functions as a transcriptional activator. The dual function of Hes-1 we have found is likely to contribute to the subtle tissue-specific control of this housekeeping gene.
Hes-1是果蝇毛状蛋白和分裂增强子蛋白的哺乳动物同源物1，属于碱性螺旋-环-螺旋蛋白家族，对神经发生、肌肉发生、造血和性别决定至关重要。正如我们之前在肝癌细胞系Hep G2中所展示的，Hes-1是包括人类酸性α-葡萄糖苷酶（GAA）基因在内的许多已知基因的转录抑制因子。人类GAA基因编码溶酶体中糖原分解的酶，其缺乏会导致II型糖原贮积病（庞贝氏症）。利用含有在Hep G2细胞中显示出抑制活性的DNA元件的构建体以及Hes-1和YY1这两种相同转录因子结合的条件，我们已经表明该元件在人类成纤维细胞中起增强子的作用。定点诱变和Hes-1的过表达表明Hes-1起着转录激活因子的作用。我们发现的Hes-1的双重功能可能有助于对这个管家基因进行微妙的组织特异性调控。
