REGULATION AND MECHANISMS OF GENE AMPLIFICATION
REGULATION AND MECHANISMS OF GENE AMPLIFICATION
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DOI：
10.1098/rstb.1995.0008
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发表时间：
1995-01-30
期刊：
影响因子：
--
通讯作者：
STARK, GR
中科院分区：
文献类型：
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作者：
SMITH, KA;AGARWAL, ML;STARK, GR
啮齿动物细胞中的扩增通常涉及桥断裂融合（BBF）循环，其由姐妹染色单体的端对端融合或由染色体断裂引发。相反，在人类细胞中，对抗代谢物N-（膦酰基乙酰基）-L-天冬氨酸（PALA）的抗性可通过几种不同的机制介导，导致靶酶氨甲酰-P合成酶、天冬氨酸转氨甲酰酶（$）在bar二氢乳清酸酶（CAD）下过表达。在人纤维肉瘤细胞系HT 1080中，涉及BBF循环的机制仅占CAD扩增事件的少数。在这里，2 p等染色体的形成和通过其他类型的扩增事件（甚至没有扩增）的CAD过表达要普遍得多。断裂的DNA被具有完整损伤识别途径的哺乳动物细胞识别，作为停止或死亡的信号。这些途径的丧失，例如p53或pRb肿瘤抑制功能的丧失，或ras和myc癌基因表达的增加，导致非允许的大鼠和人细胞变得允许扩增和DNA损伤的其他表现。在已经允许的细胞中，扩增可以通过过度表达癌基因如c-myc或ras或通过以各种方式破坏DNA来刺激。为了补充哺乳动物细胞中扩增的遗传分析，已经在粟酒裂殖酵母中建立了扩增选择。用LiCl选择产生具有与在哺乳动物细胞中观察到的结构相关的扩增的sod 2基因的细胞。对S.现在可以检测粟酒裂殖酵母中涉及受损DNA修复或正常细胞对DNA损伤反应的基因的任何突变。
Amplification in rodent cells usually involves bridge-breakage-fusion (BBF) cycles initiated either by end-to-end fusion of sister chromatids, or by chromosome breakage. In contrast, in human cells, resistance to the antimetabolite N-(phosphonacetyl)-L-aspartate (PALA) can be mediated by several different mechanisms that lead to overexpression of the target enzyme carbamyl-P synthetase, aspartate transcarbamylase, ($) under bar dihydro-orotase (CAD). Mechanisms involving BBF cycles account for only a minority of CAD amplification events in the human fibrosarcoma cell line HT 1080. Here, formation of a 2p isochromosome and overexpression of CAD by other types of amplification events (and even without amplification) are much more prevalent.Broken DNA is recognized by mammalian cells with intact damage-recognition pathways, as a signal to arrest or to die. Loss of these pathways by, for example, loss of p53 or pRb tumour suppressor function, or by increased expression of ras and myc oncogenes, causes non-permissive rat and human cells to become permissive both for amplification and for other manifestations of DNA damage. In cells that are already permissive, amplification can be stimulated by overexpressing oncogenes such as c-myc or ras, or by damaging DNA in a variety of ways. To supplement genetic analysis of amplification in mammalian cells, an amplification selection has been established in Schizosaccharomyces pombe. Selection with LiCl yields cells with amplified sod2 genes in structures related to those observed in mammalian cells. The effect on amplification in S. pombe can now be tested for any mutation in a gene involved in repair of damaged DNA or in normal cellular responses to DNA damage.