Tumor formation in mice with conditional inactivation of Brca1 in epithelial tissues
Tumor formation in mice with conditional inactivation of Brca1 in epithelial tissues
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DOI：
10.1038/sj.onc.1206825
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发表时间：
2003-08-21
期刊：
影响因子：
8
通讯作者：
Johnson, DG
中科院分区：
文献类型：
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作者：
Berton, TR;Matsumoto, T;Johnson, DG
BRCA 1肿瘤抑制蛋白与转录、DNA修复、增殖和凋亡的调节有关。BRCA 1在许多增殖性组织中表达，这至少部分是由于E2 F依赖性转录控制。在这项研究中，通过在角蛋白5（K5）启动子的控制下表达Cre重组酶，在各种上皮组织中实现了条件性鼠Brca 1等位基因的失活。K5 Cre：Brca 1条件性基因敲除小鼠表现出适度的表皮过度增殖，细胞凋亡增加，并且在1岁后易于在皮肤、内耳道和口腔上皮中发生肿瘤。在K5 Cre：Brca 1条件性基因敲除小鼠中E2 F1转录因子的过表达显著加速了肿瘤的发展。此外，E2 F1表达升高的Brca 1杂合子雌性小鼠发生生殖道肿瘤的发生率较高。这些发现表明，在小鼠中，除了乳腺外，Brca 1还在其他上皮组织中起肿瘤抑制剂的作用。此外，Brca 1的失活与Rb-E2 F1通路的失调协同作用，促进肿瘤发生。
The BRCA1 tumor-suppressor protein has been implicated in the regulation of transcription, DNA repair, proliferation, and apoptosis. BRCA1 is expressed in many proliferative tissues and this is at least in part due to E2F-dependent transcriptional control. In this study, inactivation of a conditional murine Brca1 allele was achieved in a variety of epithelial tissues via expression of the Cre recombinase under the control of a keratin 5 (K5) promoter. The K5 Cre:Brca1 conditional knockout mice exhibited modest epidermal hyperproliferation, increased apoptosis, and were predisposed to developing tumors in the skin, the inner ear canal, and the oral epithelium after 1 year of age. Overexpression of the E2F1 transcription factor in K5 Cre:Brca1 conditional knockout mice dramatically accelerated tumor development. In addition, Brca1 heterozygous female mice that had elevated E2F1 expression developed tumors of the reproductive tract at high incidence. These findings demonstrate that in mice Brca1 functions as a tumor suppressor in other epithelial tissues in addition to the mammary gland. Moreover, inactivation of Brca1 is shown to cooperate with deregulation of the Rb-E2F1 pathway to promote tumorigenesis.