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首页> 外文期刊>Molecular and Cellular Biology >Loss of Bard1, the Heterodimeric Partner of the Brca1 Tumor Suppressor, Results in Early Embryonic Lethality and Chromosomal Instability
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Loss of Bard1, the Heterodimeric Partner of the Brca1 Tumor Suppressor, Results in Early Embryonic Lethality and Chromosomal Instability

机译：Brca1肿瘤抑制物异源二聚体伴侣Bard1的缺失导致早期胚胎致死率和染色体不稳定

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摘要

The BRCA1 tumor suppressor has been implicated in many cellular pathways, but the mechanisms by which it suppresses tumor formation are not fully understood. In vivo BRCA1 forms a heterodimeric complex with the related BARD1 protein, and its enzymatic activity as a ubiquitin ligase is largely dependent upon its interaction with BARD1. To explore the genetic relationship between BRCA1 and BARD1, we have examined the phenotype of Bard1-null mice. These mice become developmentally retarded and die between embryonic day 7.5 (E7.5) and E8.5. Embryonic lethality results from a severe impairment of cell proliferation that is not accompanied by increased apoptosis. In the absence of p53, the developmental defects associated with Bard1 deficiency are partly ameliorated, and the lethality of Bard1; p53-nullizygous mice is delayed until E9.5. This result, together with the increased chromosomal aneuploidy of Bard1 mutant cells, indicates a role for Bard1 in maintaining genomic stability. The striking similarities between the phenotypes of Bard1-null, Brca1-null, and double Bard1; Brca1-null mice provide strong genetic evidence that the developmental functions of Brca1 and Bard1 are mediated by the Brca1/Bard1 heterodimer.
机译：BRCA1肿瘤抑制因子已牵涉到许多细胞途径，但其抑制肿瘤形成的机制尚不完全清楚。体内BRCA1与相关的BARD1蛋白形成异源二聚体复合物，其作为泛素连接酶的酶活性在很大程度上取决于其与BARD1的相互作用。为了探讨BRCA1和BARD1之间的遗传关系，我们检查了 Bard1 -null小鼠的表型。这些小鼠发育迟缓，在胚胎第7.5天（E7.5）至E8.5之间死亡。胚胎致死率是由细胞增殖的严重损害引起的，而细胞增殖并未伴随凋亡的增加。在缺少 p53 的情况下，与 Bard1 缺陷相关的发育缺陷得到部分缓解，并且 Bard1 具有致死性。 p53 -nullizygous小鼠被延迟到E9.5。该结果与 Bard1 突变细胞的染色体非整倍性增加，表明 Bard1 在维持基因组稳定性中的作用。 Bard1 -null， Brca1 -null和双 Bard1 的表型之间惊人的相似性; Brca1 -null小鼠提供了强有力的遗传证据，证明Brca1和Bard1的发育功能是由Brca1 / Bard1异二聚体介导的。

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