Molecular Targets of the Oncogenic Transcription Factor Jun
Molecular Targets of the Oncogenic Transcription Factor Jun
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DOI：
10.2174/1568009033333781
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发表时间：
2003-01-01
影响因子：
3
通讯作者：
Bister, K.
中科院分区：
文献类型：
--
作者：
Hartl, M.;Bader, A. G.;Bister, K.
Jun癌蛋白是转录因子复合物AP-1的主要成分，其调节细胞增殖、分化和凋亡所必需的多个基因的表达。内源性AP-1的组成性激活是禽类和哺乳动物细胞转化系统中肿瘤形成所必需的，并且也发生在不同的人类肿瘤细胞中，表明AP-1在人类肿瘤发生中起重要作用。高致癌性v-jun等位基因能够诱导禽类成纤维细胞和鸡纤维肉瘤的肿瘤转化，作为一个单一的致癌事件，产生的细胞c-jun基因在逆转录病毒转导突变。因此，禽类细胞是研究jun诱导细胞转化的分子机制的一个很好的模型系统。旨在识别基因的方法，特别是解除管制的六月转化成纤维细胞已导致识别的几个基因的致癌六月为目标。一些激活的基因代表直接转录的目标六月编码蛋白质，这可能是参与细胞的生长和分化。在v-jun转化的细胞中抑制的基因包括几种细胞外蛋白，如细胞外基质的组分或参与细胞外信号传导的蛋白。由于Jun癌蛋白对多个基因的异常调节，假设只有Jun靶基因或其子集的组合差异表达有助于正常成纤维细胞转化为肿瘤细胞，其表现出Jun诱导的细胞转化的典型表型。已经证明，不同的激活靶点在鸟类成纤维细胞中过表达后表现出部分转化活性。此外，由v-Jun沉默的不同靶基因在v-Jun转化的细胞中重新表达时抑制肿瘤形成。因此，这些转化相关基因的蛋白质产物可能是干扰jun诱导的肿瘤发生的潜在药物靶点。
The Jun oncoprotein is a major component of the transcription factor complex AP-1, which regulates the expression of multiple genes essential for cell proliferation, differentiation and apoptosis. Constitutive activation of endogenous AP-1 is required for tumor formation in avian and mammalian cell transformation systems, and also occurs in distinct human tumor cells suggesting that AP-1 plays an important role in human oncogenesis. The highly oncogenic v-jun allele capable of inducing neoplastic transformation in avian fibroblasts and fibrosarcomas in chicken as a single oncogenic event, was generated by mutation of the cellular c-jun gene during retroviral transduction. Hence, avian cells represent an excellent model system to investigate molecular mechanisms underlying jun-induced cell transformation. Approaches aimed at the identification of genes specifically deregulated in jun-transformed fibroblasts have led to the identification of several genes targeted by oncogenic Jun. Some of the activated genes represent direct transcriptional targets of Jun encoding proteins, which are presumably involved in cell growth and differentiation. Genes suppressed in v-jun-transformed cells include several extracellular proteins like components of the extracellular matrix or proteins involved in extracellular signalling. Due to aberrant regulation of multiple genes by the Jun oncoprotein, it is assumed that only the combined differential expression of Jun target genes or of a subset thereof contributes to the conversion of a normal fibroblast into a tumor cell displaying a phenotype typical of jun-induced cell transformation. It has already been shown that distinct activated targets exhibit partial transforming activity upon over-expression in avian fibroblasts. Also, distinct target genes silenced by v-Jun inhibit tumor formation when re-expressed in v-jun-transformed cells. The protein products of these transformation-relevant genes may thus represent potential drug targets for interference with jun-induced tumorigenesis.