INTEGRATED CONTROL OF CELL-PROLIFERATION AND CELL-DEATH BY THE C-MYC ONCOGENE
INTEGRATED CONTROL OF CELL-PROLIFERATION AND CELL-DEATH BY THE C-MYC ONCOGENE
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DOI：
10.1098/rstb.1994.0105
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发表时间：
1994-08-30
影响因子：
6.3
通讯作者：
BENNETT, M
中科院分区：
文献类型：
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作者：
EVAN, G;HARRINGTON, E;BENNETT, M
多细胞结构的调节涉及细胞增殖、分化和细胞死亡之间的动态平衡。细胞凋亡是一种非常迅速的活性细胞死亡的特殊形式，其特征是染色质的自毁，细胞起泡和凝结，以及内部成分的泡化。c-myc原癌基因编码细胞增殖机制的重要组成部分，其不受调控的表达与大多数肿瘤有关。有趣的是，c-myc也可以作为细胞凋亡的有效诱导剂。myc诱导的细胞凋亡仅发生在缺乏生长因子或被细胞抑制药物强制抑制的细胞中。myc诱导的细胞凋亡取决于其表达水平，缺失图谱显示，凋亡所需的c-Myc区域与共转化、自动调节、抑制分化、转录激活和序列特异性DNA结合所需的区域重叠。此外，c-Myc诱导细胞凋亡需要与c-Myc的异源伴侣Max相关联。所有这些都强烈暗示c-Myc通过转录机制驱动细胞凋亡：可能是通过调节靶基因。两个简单的模型可以用来解释c-Myc诱导细胞凋亡。一种观点认为，死亡是由生长信号的冲突引起的，这种冲突是由c-Myc在通常会促进生长停滞的条件下不适当或计划外的表达所产生的。在这个“冲突”模型中，诱导凋亡不是c-Myc的正常功能，而是其失调的病理表现。因此，它只对myc基因总是被破坏的致癌进展模型有意义。另一种模型认为，诱导凋亡是c-Myc的正常专性功能，受特定存活因子的调节。因此，每个进入周期的细胞都调用了一个专性中止自杀途径，该途径必须被来自直接细胞环境的信号持续抑制，以使增殖细胞存活。本文将提出支持细胞生长和存活的第二种“双信号”模型的证据，并讨论其广泛的影响。
Regulation of multicellular architecture involves a dynamic equilibrium between cell proliferation, differentiation with consequent growth arrest, and cell death. Apoptosis is one particular form of active cell death that is extremely rapid and characterized by auto-destruction of chromatin, cellular blebbing and condensation, and vesicularization of internal components.The c-myc proto-oncogene encodes an essential component of the cell's proliferative machinery and its deregulated expression is implicated in most neoplasms. Intriguingly, c-myc can also act as a potent inducer of apoptosis. Myc-induced apoptosis occurs only in cells deprived of growth factors or forcibly arrested with cytostatic drugs. Myc-induced apoptosis is dependent upon the level at which it is expressed and deletion mapping shows that regions of c-Myc required for apoptosis overlap with regions necessary for co-transformation, autoregulation, inhibition of differentiation, transcriptional activation and sequence-specific DNA binding. Moreover, induction of apoptosis by c-Myc requires association with c-Myc's heterologous partner, Max. All of this strongly implies that c-Myc drives apoptosis through a transcriptional mechanism: presumably by modulation of target genes.Two simple models can be invoked to explain the induction of apoptosis by c-Myc. One holds that death arises from a conflict in growth signals which is generated by the inappropriate or unscheduled expression of c-Myc under conditions that would normally promote growth arrest. In this 'Conflict' model, induction of apoptosis is not a normal function of c-Myc but a pathological manifestation of its deregulation. It thus has significance only for models of carcinogenic progression in which myc genes are invariably disrupted. The other model holds that induction of apoptosis is a normal obligate function of c-Myc which is modulated by specific survival factors. Thus, every cell that enters the cycle invokes an obligate abort suicide pathway which must be continuously suppressed by signals from the immediate cellular environment for the proliferating cell to survive. Evidence will be presented supporting this second 'Dual Signal' model for cell growth and survival, and its widespread implications will be discussed.