文章：

核糖体翻译癌症吗？

Does the ribosome translate cancer?

原文发布日期：2003-03-01

DOI: 10.1038/nrc1015

类型: Review Article

开放获取: 否

要点：

1. Ribosome biogenesis and translation are regulated at multiple levels and are associated with accurate cell growth and proliferation. The loss of key checkpoints during protein synthesis might contribute to the initiation and progression of cancer.
2. During specific phases of the cell cycle, the synthesis of rRNA, as well as components of the protein synthesis machinery, is initiated by the phosphorylation of key transcription factors that regulate polymerase I (Pol I) and Pol III activity, respectively. This tight link between cell-cycle progression and protein synthesis exists to ensure accurate cell growth and proliferation, which might be lost in cancer cells.
3. p53 and retinoblastoma (RB) repress Pol I and Pol III transcription. In cancer cells, which harbour inactivating mutations in these tumour suppressors, deregulation of Pol I and Pol III activity might contribute to tumorigenesis.
4. Several ribosomal proteins are overexpressed in a variety of tumours. It remains to be determined whether this represents a cause or consequence of tumour formation. Increased phosphorylation of the S6 ribosomal protein is thought to result in enhanced translation of specific mRNAs. This raises the possibility that deregulation of ribosomal proteins in tumours might affect the translation of specific target mRNAs.
5. MYC and PTEN act as master regulators of ribosome biogenesis and translation control. Their deregulation in tumour cells increases the expression and activity of components of the translation apparatus. It remains to be determined which of the downstream targets of MYC and PTEN involved in controlling protein synthesis are directly responsible for tumour susceptibility.
6. Further investigation will be needed to clarify to what extent deregulation in total or specific translation of mRNAs contributes to tumorigenesis. Although mutations in genes that are directly responsible for ribosome biogenesis, such as those encoding the ribosomal protein S19 and DKC1 (the enzyme that modifies rRNA), have been found in cancer susceptibility syndromes, the molecular mechanisms by which these proteins cause cancer remain largely unknown.
7. Components of the translation machinery that are overexpressed or deregulated in cancer cells could represent targets for cancer therapy. The macrolide rapamycin, which affects the translation machinery, has already been used in clinical trials as a tumour inhibitory agent.

要点翻译：

1. 核糖体生物合成与翻译过程在多个层面受到精密调控，这些过程与细胞正常的生长增殖密切相关。蛋白质合成关键检查点的缺失可能参与肿瘤的发生与发展。
2. 在细胞周期特定阶段，rRNA及蛋白质合成机制相关组分的合成分别通过调控聚合酶I（Pol I）和Pol III活性的关键转录因子磷酸化而启动。这种细胞周期进程与蛋白质合成之间的紧密联系确保了细胞生长增殖的精确性，而该机制在癌细胞中可能丧失功能。
3. p53与视网膜母细胞瘤（RB）蛋白可抑制Pol I和Pol III的转录活性。在携带这些抑癌基因失活突变的癌细胞中，Pol I和Pol III活性的失调可能促进肿瘤发生。
4. 多种核糖体蛋白在肿瘤组织中过度表达，这种现象究竟是肿瘤形成的原因还是后果仍有待阐明。核糖体蛋白S6磷酸化水平升高被认为可增强特定mRNA的翻译效率，这提示肿瘤中核糖体蛋白的失调可能影响特定靶标mRNA的翻译过程。
5. MYC和PTEN作为核糖体生物合成与翻译调控的核心枢纽，其在肿瘤细胞中的功能失调会提升翻译装置各组分的表达与活性。目前尚需明确MYC和PTEN下游参与蛋白质合成调控的靶点中哪些直接导致肿瘤易感性。
6. 未来研究需明确mRNA整体或特异性翻译失调对肿瘤发生发展的影响程度。尽管在癌症易感综合征中已发现直接参与核糖体生物合成的基因（如编码核糖体蛋白S19和rRNA修饰酶DKC1的基因）存在突变，但这些蛋白质致癌的分子机制仍 largely 未知。
7. 癌细胞中过度表达或功能失调的翻译机制组分可能成为癌症治疗的靶点。大环内酯类雷帕霉素可通过影响翻译机制发挥抗肿瘤作用，目前已进入临床试验阶段。

英文摘要：

Ribosome biogenesis and translation control are essential cellular processes that are governed at numerous levels. Several tumour suppressors and proto-oncogenes have been found either to affect the formation of the mature ribosome or to regulate the activity of proteins known as translation factors. Disruption in one or more of the steps that control protein biosynthesis has been associated with alterations in the cell cycle and regulation of cell growth. Therefore, certain tumour suppressors and proto-oncogenes might regulate malignant progression by altering the protein synthesis machinery. Although many studies have correlated deregulation of protein biosynthesis with cancer, it remains to be established whether this translates directly into an increase in cancer susceptibility, and under what circumstances.

摘要翻译： 

核糖体生物合成与翻译控制是受到多层次调控的必需细胞过程。已发现若干肿瘤抑制基因和原癌基因既可影响成熟核糖体的形成，也可调节被称为翻译因子的蛋白质的活性。蛋白质生物合成调控步骤中的一个或多个环节发生紊乱，与细胞周期和细胞生长调控的改变相关。因此，某些肿瘤抑制基因和原癌基因可能通过改变蛋白质合成机制来调控恶性进展。尽管许多研究已将蛋白质生物合成的失调与癌症相关联，但是否这直接导致癌症易感性增加，以及在何种情况下发生，仍有待确定。

原文链接：

Does the ribosome translate cancer?