The hairless promoter is differentially regulated by thyroid hormone in keratinocytes and neuroblastoma cells
The hairless promoter is differentially regulated by thyroid hormone in keratinocytes and neuroblastoma cells
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DOI：
10.1111/j.0906-6705.2004.00175.x
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发表时间：
2004-04-01
影响因子：
3.6
通讯作者：
Christiano, AM
中科院分区：
文献类型：
--
作者：
Engelhard, A;Christiano, AM
毛发周期是一个非常复杂的过程，依赖于细胞间信号传导、细胞分裂和死亡、细胞迁移和基因表达的空间和时间协调整合。无毛基因（hr）的表达具有毛发周期依赖性，hr的致病性突变导致小鼠的无毛和犀牛表型以及人类的无毛伴丘疹病变。除了在皮肤和毛囊中表达外，hr在大脑中也高度表达，但控制其差异细胞类型特异性表达的因素尚未确定。以前在大鼠hr启动子中鉴定了甲状腺激素响应元件，其赋予甲状腺激素（T3）对异源启动子构建体的响应性;然而，以前的研究没有集中在hr启动子本身。克隆了无毛启动子，结果表明，hr启动子在神经母细胞瘤细胞中被T3反式激活，但在角质形成细胞中不被激活。因此，虽然T3在无毛的神经元表达的调节中具有重要作用，但其在角质形成细胞中的上调是T3独立的。此外，hr受细胞类型特异性负性自身调节，抑制其自身启动子在角质形成细胞中的活性，但不抑制神经母细胞瘤细胞。这些发现说明了在确定的细胞群体中hr表达调控的分子差异。
The hair cycle is an extraordinarily complex process relying on spatially and temporally coordinated integration of intercellular signaling, cell division and death, cell migration, and gene expression. The hairless gene (hr) is expressed with hair-cycle-dependent kinetics, and pathogenic mutations in hr are responsible for the hairless and rhino phenotypes in mice and atrichia with papular lesions in humans. In addition to its expression in the skin and hair follicle, hr is also highly expressed in the brain, yet the factors governing its differential cell-type-specific expression have not yet been defined. A thyroid hormone responsive element was previously identified in the rat hr promoter which confers thyroid hormone (T3) responsiveness to heterologous promoter constructs; however, prior studies have not focused on the hr promoter itself. The hairless promoter was cloned, and it is shown that the hr promoter is transactivated by T3 in neuroblastoma cells but not in keratinocytes. Therefore, while T3 has a significant role in the regulation of neuronal expression of hairless, its upregulation in keratinocytes is T3 independent. Furthermore, hr is subject to cell-type-specific negative autoregulation, inhibiting the activity of its own promoter in keratinocytes but not neuroblastoma cells. These findings illustrate a molecular distinction between the regulation of hr expression in defined cell populations.