Cathepsin B expression in human tumors.
Cathepsin B expression in human tumors.
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DOI：
10.1007/978-1-4613-0335-0_35
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发表时间：
1996
影响因子：
--
通讯作者：
I. Berquin;Bonnie F. Sloane
中科院分区：
文献类型：
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作者：
I. Berquin;Bonnie F. Sloane
组织蛋白酶B通过观察其活性、分泌或膜结合增加而与肿瘤进展相关。最恶性的肿瘤，特别是那些肿瘤侵袭边缘的细胞，表达最高的活性。组织蛋白酶B可以通过溶解细胞外基质屏障（如基底膜）直接促进侵袭，或者通过激活能够消化细胞外基质的其他蛋白酶间接促进侵袭。组织蛋白酶B也可能在肿瘤生长和血管生成中起作用。组织蛋白酶B活性是几个水平调节的结果：转录、转录后加工、翻译和糖基化、成熟和运输以及抑制。关于肿瘤中组织蛋白酶B表达的大多数报道集中于活性或蛋白质染色的测量。在一些肿瘤中，例如，在神经胶质瘤中，已经建立了组织蛋白酶B mRNA、蛋白质和活性的量与肿瘤进展之间的相关性。组织蛋白酶B在转录和转录后水平的调控仍然知之甚少。虽然推定的启动子区域具有管家型启动子的特征，但组织蛋白酶B mRNA表达根据细胞类型和分化状态而变化。我们有证据表明不止一个启动子可以指导人组织蛋白酶B的表达。已经检测到多种转录物种类，这是由于5′-和3′-非翻译区的选择性剪接，以及可能使用了选择性启动子区。转录变体的存在表明了表达的转录后控制的潜力。为了支持这一点，MCF-10A人乳腺上皮细胞的ras转化导致蛋白质水平增加，而mRNA水平没有伴随增加。具有不同5′-或3′-非翻译区的组织蛋白酶B mRNA种类在其稳定性和可翻译性方面可能不同。编码区的变异也可能改变组织蛋白酶B的性质。我们和Frankfater的小组已经观察到了编码截短蛋白质的转录物种类，缺少前肽和大约一半的前肽。这种截短的蛋白质，如果在细胞中合成，预计将是胞质的;因此其功能尚不清楚。一旦更好地理解了组织蛋白酶B表达和活性的几种调节机制，它们可以为我们提供新的策略来特异性地降低肿瘤中的组织蛋白酶B活性。
Cathepsin B has been linked to tumor progression through observations that its activity, secretion or membrane association are increased. The most malignant tumors, and specifically the cells at the invasive edge of those tumors, express the highest activity. Cathepsin B may facilitate invasion directly by dissolving extracellular matrix barriers like the basement membrane, or indirectly by activating other proteases capable of digesting the extracellular matrix. Cathepsin B also might play a role in tumor growth and angiogenesis. Cathepsin B activity is the result of several levels of regulation: transcription, post-transcrip-tional processing, translation and glycosylation, maturation and trafficking, and inhibition. The majority of reports on cathepsin B expression in tumors have focused on measurements of activity or protein staining. In some tumors, e.g., gliomas, a correlation between the amounts of cathepsin B mRNA, protein and activity and tumor progression has been established. Regulation of cathepsin B at the transcriptional and post-transcriptional levels is still poorly understood. Although the putative promoter regions have characteristics of housekeeping-type promoters, cathepsin B mRNA expression varies depending on the cell type and state of differentiation. We have evidence that more than one promoter could direct expression of human cathepsin B. Multiple transcript species have been detected, resulting from alternative splicing in the 5′- and 3′-untranslated regions, and possibly the use of alternative promoter regions. The existence of transcript variants indicates a potential for post-transcriptional control of expression. In support of this, ras-transformation of MCF-10A human breast epithelial cells results in an increase in protein levels without a concomitant increase in mRNA levels. Cathepsin B mRNA species with distinct 5′-or 3′-untranslated regions may differ in their stability and translatability. Variations in the coding region may also alter cathepsin B properties. We and Frankfater’s group have observed transcript species that would encode a truncated protein, lacking the prepeptide and about half of the propeptide. This truncated protein, if synthesized in cells, would be expected to be cytosolic; therefore its function is unclear. Once the several mechanisms of regulation of cathepsin B expression and activity are better understood, they could provide us with new strategies to specifically reduce cathepsin B activity in tumors.