Lymphoma development in Bax transgenic mice is inhibited by Bcl-2 and associated with chromosomal instability
Lymphoma development in Bax transgenic mice is inhibited by Bcl-2 and associated with chromosomal instability
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DOI：
10.1038/sj.cdd.4401233
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发表时间：
2003-06-01
影响因子：
12.4
通讯作者：
Knudson, CM
中科院分区：
文献类型：
--
作者：
Luke, JJ;van de Wetering, CI;Knudson, CM
Bax是Bcl-2家族成员，促进细胞凋亡，但对p53缺陷小鼠淋巴瘤的发展有矛盾的影响。为了更好地理解Bax诱导的淋巴瘤发展的机制，确定Bax水平、p53状态和Bcl-2共表达对淋巴瘤发展的影响。此外，DNA含量和细胞遗传学进行了年轻（癌前）LCK-Bax小鼠的遗传不稳定性的措施。Bax以剂量依赖性方式促进p53缺陷小鼠淋巴瘤的发展。Bax表达也导致p53 +/-和+/+动物的淋巴瘤发展。在明显的胸腺淋巴瘤发作之前对小鼠进行的倍性分析表明，Lck-Bax转基因小鼠更可能是非整倍体，并表现出增加的染色体不稳定性。随着肿瘤进展，非整倍体增加，Bax表达维持不变。重要的是，Bcl-2的共表达延迟了Lck-Bax转基因小鼠中淋巴瘤的发展。这些数据支持一种模型，其中对细胞凋亡的敏感性增加直接导致发育中T细胞的染色体不稳定性，并可能解释一些关于Bcl-2家族成员和癌症调控的矛盾观察。
Bax is a Bcl-2 family member that promotes apoptosis but has paradoxical effects on lymphoma development in p53-deficient mice. To better understand the mechanism of Bax-induced lymphoma development, the effect of Bax levels, p53 status and Bcl-2 coexpression on lymphoma development were determined. In addition, DNA content and cytogenetics were performed on young ( premalignant) Lck-Bax mice as measures of genetic instability. Bax promoted lymphoma development in p53-deficient mice in a dose-dependent manner. Bax expression also led to lymphoma development in both p53 +/- and +/+ animals. Ploidy analysis in mice prior to the onset of overt thymic lymphomas demonstrated that Lck-Bax transgenic mice were more likely to be aneuploid and demonstrate increased chromosome instability. With tumor progression, aneuploidy increased and Bax expression was maintained. Importantly, coexpression of Bcl-2 delayed lymphoma development in Lck-Bax transgenic mice. These data support a model in which increased sensitivity to apoptosis leads directly to chromosome instability in developing T cells and may explain a number of paradoxical observations regarding Bcl-2 family members and the regulation of cancer.