Distinct promoters regulate tissue-specific and differential expression of kallikrein 6 in CNS demyelinating disease
Distinct promoters regulate tissue-specific and differential expression of kallikrein 6 in CNS demyelinating disease
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DOI：
10.1111/j.1471-4159.2004.02826.x
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发表时间：
2004-12-01
影响因子：
4.7
通讯作者：
Scarisbrick, IA
中科院分区：
文献类型：
--
作者：
Christophi, GP;Jackson, PJ;Scarisbrick, IA
激肽释放酶6是一种丝氨酸蛋白酶，在正常成人和啮齿动物中枢神经系统中大量表达，并受到损伤的调节。在中枢神经系统脱髓鞘疾病的情况下，中枢神经系统中的 K6 表达另外出现在血管周围和实质炎症细胞中，表明在发病机制中发挥作用。在此，我们描述了人类和小鼠 K6 基因中存在的两个独特转录本，它们的 5'-非翻译区有所不同。这些转录物在外显子 3 中具有相同的翻译起始位点，以组织特异性方式表达，并针对中枢神经系统损伤进行差异调节。虽然人类和小鼠 5' 转录本的序列不同，但它们在基因组组织和组织特异性表达方面是相同的。最靠近的 5'-转录本（称为转录本 1）包括外显子 1-7，并且在所有 CNS 区域中均可检测到，但在所检查的任何非 CNS 组织（脾、胸腺、肝、肾、胰腺、颌下腺和周围神经）中均未检测到。相反，转录本 2 缺少外显子 1，但在外显子 2 的 5' 端包含独特的序列，指定为外显子 2A。转录本2在CNS和每个外周组织中都有表达。在由泰勒小核糖核酸病毒诱导的人类中枢神经系统脱髓鞘炎症疾病的小鼠模型中，在中枢神经系统炎症和脱髓鞘的急性和慢性阶段，小鼠 K6 转录物 1 在大脑和脊髓中上调，而总体转录物 2 表达没有显着改变。然而，在分离的脾细胞培养物中，转录物 2 通过细胞激活上调两倍。 CNS 疾病中的组织特异性表达模式和差异调节表明，每个 K6 5'-转录物可能受到独特的启动子元件的调节，并且可以作为治疗炎症性脱髓鞘疾病的分子靶标。
Kallikrein 6 is a serine protease expressed abundantly in normal adult human and rodent CNS, and therein is regulated by injury. In the case of CNS demyelinating disease, K6 expression in CNS occurs additionally in perivascular and parenchymal inflammatory cells suggesting a role in pathogenesis. Herein we describe two unique transcripts that occur within the human and mouse K6 genes that differ in their 5'-untranslated regions. These transcripts have identical translation initiation sites in exon 3, are expressed in a tissue-specific fashion and are differentially regulated in response to CNS injury. While the human and mouse 5'-transcripts differ in sequence they are identical in genomic organization and tissue-specific expression. The most 5'-transcript, designated transcript 1, includes exon 1-7, and was detectable in all CNS regions, but not in any non-CNS tissues examined (spleen, thymus, liver, kidney, pancreas, submandibular gland and peripheral nerve). In contrast, transcript 2 lacks exon 1, but contains a unique sequence at the 5'-end of exon 2, designated exon 2A. Transcript 2 was expressed both in CNS and in each peripheral tissue. In a murine model of human CNS demyelinating inflammatory disease induced by Theiler's picornovirus, mouse K6 transcript 1 was up-regulated in brain and spinal cord at acute and more chronic phases of CNS inflammation and demyelination, while overall transcript 2 expression was not significantly altered. However, in isolated splenocyte cultures, transcript 2 was up-regulated two-fold by cellular activation. Tissue-specific expression patterns and differential regulation in CNS disease indicates that each K6 5'-transcript is probably regulated by unique promoter elements and may serve as a molecular target to treat inflammatory demyelinating disease.