Little E, Ramakrishnan M, Roy B, Gazit G, Lee A S
Department of Biochemistry and Molecular Biology, University of Southern California School of Medicine, Los Angeles 90033.
Crit Rev Eukaryot Gene Expr. 1994;4(1):1-18. doi: 10.1615/critreveukargeneexpr.v4.i1.10.
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.
作为分子伴侣的葡萄糖调节蛋白（GRP）的相关知识正在迅速发展。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，它们可能作为一类受源自内质网并传导至细胞核的信号转导途径调控的基因的原型发挥作用。GRP78和GRP94作为分子伴侣，能够结合错误折叠的蛋白质和未组装的复合物。它们在应激反应中被诱导产生，但一旦应激消除，GRP就会在转录后被修饰为无生物学活性的形式。grp基因的启动子高度保守，具有多个类CCAAT基序和富含GC的区域。哺乳动物grp启动子中存在的高度冗余可能起到确保这两个单拷贝基因的表达在发生突变时不太可能显著降低的作用。这些基因被认为受几种转录因子控制，这些转录因子与grp启动子的复杂相互作用允许grp诱导产生可变模式。grp基因的启动子持续表达其基因产物，并且在低葡萄糖或低氧的细胞环境中其启动子活性可以进一步增强。已知grp78启动子在分化和未分化组织中都保持其强大的活性。这些特性使其成为基因治疗中用于替代病毒启动子的有吸引力的选择。基因治疗在某些情况下，尤其是实体瘤的治疗中可能也很有用。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。也许通过反义或核酶技术抑制GRP诱导，可能证明与抗癌药物联合使用对治疗肿瘤有用。
