Felsher D W, Bishop J M
Division of Hematology-Oncology, Department of Medicine, University of California, San Francisco 94143-1270, USA.
Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3940-4. doi: 10.1073/pnas.96.7.3940.
Overexpression of the MYC protooncogene has been implicated in the genesis of diverse human tumors. Tumorigenesis induced by MYC has been attributed to sustained effects on proliferation and differentiation. Here we report that MYC may also contribute to tumorigenesis by destabilizing the cellular genome. A transient excess of MYC activity increased tumorigenicity of Rat1A cells by at least 50-fold. The increase persisted for >30 days after the return of MYC activity to normal levels. The brief surfeit of MYC activity was accompanied by evidence of genomic instability, including karyotypic abnormalities, gene amplification, and hypersensitivity to DNA-damaging agents. MYC also induced genomic destabilization in normal human fibroblasts, although these cells did not become tumorigenic. Stimulation of Rat1A cells with MYC accelerated their passage through G1/S. Moreover, MYC could force normal human fibroblasts to transit G1 and S after treatment with N-(phosphonoacetyl)-L-aspartate (PALA) at concentrations that normally lead to arrest in S phase by checkpoint mechanisms. Instead, the cells subsequently appeared to arrest in G2. We suggest that the accelerated passage through G1 was mutagenic but that the effect of MYC permitted a checkpoint response only after G2 had been reached. Thus, MYC may contribute to tumorigenesis through a dominant mutator effect.
MYC原癌基因的过表达与多种人类肿瘤的发生有关。MYC诱导的肿瘤发生归因于对细胞增殖和分化的持续影响。在此我们报告，MYC也可能通过破坏细胞基因组的稳定性来促进肿瘤发生。短暂的MYC活性过剩使Rat1A细胞的致瘤性增加了至少50倍。在MYC活性恢复到正常水平后，这种增加持续了超过30天。MYC活性的短暂过剩伴随着基因组不稳定的证据，包括核型异常、基因扩增以及对DNA损伤剂的超敏反应。MYC也在正常人成纤维细胞中诱导基因组不稳定，尽管这些细胞没有变成致瘤性细胞。用MYC刺激Rat1A细胞加速了它们通过G1/S期的进程。此外，在通常会通过检查点机制使细胞停滞在S期的浓度下用N-(膦酰乙酰基)-L-天冬氨酸（PALA）处理后，MYC能迫使正常人成纤维细胞通过G1期和S期。相反，这些细胞随后似乎停滞在G2期。我们认为，加速通过G1期具有致突变性，但MYC的作用仅在到达G2期后才允许产生检查点反应。因此，MYC可能通过显性突变效应促进肿瘤发生。
