The glucose-regulated proteins (GRP78 and GRP94): functions, gene regulation, and applications.
The glucose-regulated proteins (GRP78 and GRP94): functions, gene regulation, and applications.
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DOI：
10.1615/critreveukargeneexpr.v4.i1.10
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发表时间：
1994
影响因子：
1.6
通讯作者：
E. Little;Meera Ramakrishnan;Binayak Roy;G. Gazit;Amy S. Lee
中科院分区：
文献类型：
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作者：
E. Little;Meera Ramakrishnan;Binayak Roy;G. Gazit;Amy S. Lee
GRP作为分子伴侣的知识正在迅速发展。预计GRP将在基础细胞生物学、生物技术和癌症生物学领域做出特殊贡献。特别是，它们可能作为一类基因的原型发挥作用，这些基因由起源于ER并行进到细胞核的信号转导途径调节。GRP78和GRP94起分子伴侣的作用，可以与错误折叠的蛋白质和未组装的复合物结合。它们在应激反应中被诱导，但一旦应激被消除，GRP就会被转录后修饰成生物学上无活性的形式。grp基因的启动子是高度保守的，具有几个CCAAT样基序和富含GC的区域。存在于哺乳动物grp启动子中的高水平冗余可能起到确保基因表达的作用，这两个基因都是单拷贝的，在突变的情况下不太可能显著降低。这些基因被认为是由几个转录因子控制的，这些转录因子与grp启动子的复杂相互作用允许grp诱导的可变模式。grp基因的启动子组成型表达其基因产物，并且它们的启动子活性可以在低糖或低氧的细胞环境中进一步增强。已知grp78启动子在分化和未分化组织中保持其强活性。这些特征使其成为用于基因治疗的病毒启动子的有吸引力的替代物。在某些情况下，基因疗法也可用于治疗癌症，特别是实体瘤。在这些情况下，GRP水平可能已经相当高。这些高水平的GRP可能会抑制几种抗癌治疗的疗效。抑制GRP诱导，也许是通过反义或核酶技术，可能被证明是有用的抗癌药物结合治疗肿瘤。
The knowledge of GRPs as molecular chaperones is rapidly evolving. It is anticipated that the GRPs will make special contributions in the areas of basic cell biology, biotechnology, and cancer biology. In particular, they may play a role as the prototype of a class of genes that are regulated by signal transduction pathways originating in the ER and traveling to the nucleus. GRP78 and GRP94 function as molecular chaperones and can bind to malfolded proteins and unassembled complexes. They are induced in response to stress, but once the stress is removed the GRPs are posttranscriptionally modified into biologically inactive forms. The promoters of the grp genes are highly conserved, with several CCAAT-like motifs and GC-rich regions. The high level of redundancy that exists in the mammalian grp promoters may act to ensure that the expression of the genes, both of which are single copy, is unlikely to be significantly lowered in the event of mutation. These genes are thought to be controlled by several transcription factors whose complex interactions with the grp promoters allow variable patterns of grp induction. The promoters of the grp genes constitutively express their gene products, and their promoter activities can be further enhanced in cellular environments of low glucose or oxygen. The grp78 promoter is known to retain its strong activity in differentiated and undifferentiated tissues. These features make it an attractive alternative to viral promoters for use in gene therapy. Gene therapy may also be useful in treating cancer in some cases, especially solid tumors. In these instances, GRP levels are already likely to be quite high. These high levels of GRPs may inhibit the efficacy of several anti-cancer treatments. Suppression of GRP induction, perhaps by anti-sense or ribozyme technology, may prove to be useful in conjunction with anti-cancer drugs to treat tumors.