文章：

c-MYC：不仅仅是生与死的问题

c-MYC: more than just a matter of life and death

原文发布日期：2002-10-01

DOI: 10.1038/nrc904

类型: Review Article

开放获取: 否

要点：

1. The proto-oncogene c-MYC encodes a transcription factor that is implicated in various cellular processes? cell growth, proliferation, loss of differentiation and apoptosis.
2. c-MYC activates a variety of known target genes as part of a heterodimeric complex with the protein MAX. For example, cyclin D2 and CDK2 are essential for cell-cycle progression, and translation initiation factors eIF4 and eIF2 are important in cell growth.
3. MYC?MAX heterodimers regulate gene activation through chromatin remodelling: association with co-activator TRRAP, which contains HAT activity, leads to acetylation of nucleosomal histones.
4. c-MYC inhibits the differentiation of many cell types. Conversely, MAD/MXI1 transcription factors promote differentiation by antagonizing c-MYC function by forming dimers with MAX. MAD? MAX dimers recruit corepressors (such as SIN3) and HDACs to target DNA, leading to histone deacetylation and subsequent repression of MYC target genes.
5. c-MYC sensitizes cells to a wide range of pro-apoptotic stimuli in vitro via cytochrome c release from mitochondria and subsequent formation of the apoptosome with APAF1 and procaspase-9.
6. Oncogenic c-MYC implies constitutive or deregulated expression of c-MYC that is no longer dependent on external signals and is associated with many human cancers.
7. Conditional transgenic mice, which allow regulated activation of c-MYC in distinct tissues (epidermis and pancreatic islets), have highlighted which cellular response attributed to c-MYC alone (proliferation or apoptosis) predominates in intact tissues in vivo.
8. Regulatable c-MYC transgenic mouse models of cancer have highlighted oncogenic properties of c-MYC in vivo when its apoptotic pathway is blocked, which include induction of angiogenesis, loss of cell?cell contacts and local tissue invasion.
9. Conditional mouse transgenic systems have ascertained when cancer-initiating oncogenic mutations (such as c-MYC and RAS) remain essential for maintenance of the established tumour in vivo. These findings are important for the development of candidate drug molecules that are directed against the oncoprotein.

要点翻译：

1. 原癌基因c-MYC编码一种转录因子，该因子参与多种细胞过程——细胞生长、增殖、分化能力丧失及细胞凋亡。
2. c-MYC与MAX蛋白形成异源二聚体复合物，激活多种已知靶基因。例如细胞周期进展必需的细胞周期蛋白D2和CDK2，以及细胞生长中至关重要的翻译起始因子eIF4和eIF2。
3. MYC-MAX异源二聚体通过染色质重塑调控基因激活：与具有组蛋白乙酰转移酶活性的共激活因子TRRAP结合，导致核小体组蛋白乙酰化。
4. c-MYC抑制多种细胞类型的分化。相反，MAD/MXI1转录因子通过与MAX形成二聚体拮抗c-MYC功能，从而促进分化。MAD-MAX二聚体招募辅抑制因子（如SIN3）和组蛋白去乙酰化酶至靶DNA，导致组蛋白去乙酰化和MYC靶基因的后续抑制。
5. c-MYC通过诱导线粒体释放细胞色素c，并与APAF1及半胱天冬酶原-9形成凋亡体，使体外培养细胞对多种促凋亡刺激敏感。
6. 致癌性c-MYC意味着其表达呈现持续性或失控性，不再依赖外部信号，与多种人类癌症相关。
7. 通过在特定组织（表皮和胰岛）中可调控激活c-MYC的条件性转基因小鼠模型，研究揭示了在体内完整组织中c-MYC单独主导的细胞应答（增殖或凋亡）何种占优势。
8. 可调控的c-MYC转基因癌症小鼠模型证实，当其凋亡通路被阻断时，c-MYC在体内表现出诱导血管生成、丧失细胞间连接和局部组织侵袭等致癌特性。
9. 条件性小鼠转基因系统已确定，当致癌起始突变（如c-MYC和RAS）在体内对已形成肿瘤的维持持续起关键作用时，这一发现对开发针对致癌蛋白的候选药物分子具有重要意义。

英文摘要：

Deregulated expression of c-MYC occurs in a broad range of human cancers and is often associated with poor prognosis, indicating a key role for this oncogene in tumour progression. However, as established human tumours often bear multiple genetic lesions, it is difficult to determine whether c-MYC is instrumental in the initiation/progression of the tumour, or indeed whether inactivating c-MYC would lead to tumour regression. Regulatable transgenic mouse models of oncogenesis have shed light on these issues and provide hope for effective cancer therapies.

摘要翻译： 

c-MYC 的异常表达可见于多种人类癌症，且常与不良预后相关，提示该癌基因在肿瘤进展中起关键作用。然而，由于已建立的人类肿瘤往往携带多重遗传损伤，难以确定 c-MYC 是否在肿瘤的起始/进展中起决定性作用，也不清楚失活 c-MYC 是否能导致肿瘤消退。可调控的转基因肿瘤发生小鼠模型为这些难题提供了线索，并为有效的癌症治疗带来了希望。

原文链接：

c-MYC: more than just a matter of life and death