Geng Chuan-dong, Schwartz Jason R, Vedeckis Wayne V
Department of Biochemistry and Molecular Biology, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
Mol Endocrinol. 2008 Dec;22(12):2624-42. doi: 10.1210/me.2008-0157. Epub 2008 Oct 22.
Glucocorticoid (GC) hormones are widely used in the treatment of acute lymphoblastic leukemia (ALL). Whereas a high level of GC receptor (GR) protein is associated with the sensitivity of ALL cells to steroid-mediated apoptosis, the auto-up-regulation of human (h)GR mRNA and protein is also found in hormone-sensitive ALL cell lines. We have characterized the hGR gene-proximal promoters for DNA sequences and transcription factors required for hormone responsiveness in T lymphoblasts. Sequences at -4559/-4525 and -2956/-2916, relative to the translation start site, function as strong composite GC response units (GRUs). Both GRUs include adjacent protein recognition sequences for the c-Myb transcription factor and the GR as a DNA cassette. An Ets-binding sequence overlaps the GR-binding site in the -4559/-4525 GRU, whereas an Ets-binding site present in the -2956/-2916 GRU does not overlap the GR/c-Myb-binding cassette. The Ets protein family member, PU.1, blocks hormonal activation of the -4559/-4525 GR/c-Myb-binding cassette but does not interfere with the responsiveness of the -2956/-2916 GRU. Thus, the hGR 1A GRU (described previously), the -4559/-4525 GRU, and the -2956/-2916 GRU have a similar structure and can mediate cell type-specific hormonal auto-up-regulation of hGR promoter activity in steroid-sensitive ALL cells. However, subtle differences in the GRU architecture result in differential sensitivity of the promoters to Ets family members such as PU.1. The architecture of the GRU and the spectrum of specific transcription factors present in different types of ALL might allow the development of a tailored therapy to enhance steroid sensitivity in ALL patients.
糖皮质激素（GC）激素广泛用于急性淋巴细胞白血病（ALL）的治疗。虽然高水平的糖皮质激素受体（GR）蛋白与ALL细胞对类固醇介导的凋亡敏感性相关，但在激素敏感的ALL细胞系中也发现了人（h）GR mRNA和蛋白的自身上调。我们已经鉴定了hGR基因近端启动子中T淋巴母细胞激素反应所需的DNA序列和转录因子。相对于翻译起始位点，-4559/-4525和-2956/-2916处的序列作为强大的复合GC反应单元（GRU）发挥作用。两个GRU都包括相邻的c-Myb转录因子和GR作为DNA盒的蛋白质识别序列。一个Ets结合序列与-4559/-4525 GRU中的GR结合位点重叠，而-2956/-2916 GRU中存在的一个Ets结合位点不与GR/c-Myb结合盒重叠。Ets蛋白家族成员PU.1阻断-4559/-4525 GR/c-Myb结合盒的激素激活，但不干扰-2956/-2916 GRU的反应性。因此，hGR 1A GRU（先前已描述）、-4559/-4525 GRU和-2956/-2916 GRU具有相似的结构，并且可以介导类固醇敏感的ALL细胞中hGR启动子活性的细胞类型特异性激素自身上调。然而，GRU结构的细微差异导致启动子对Ets家族成员（如PU.1）的敏感性不同。GRU的结构和不同类型ALL中存在的特定转录因子谱可能允许开发定制疗法以增强ALL患者的类固醇敏感性。
