Functional Interaction of BRCA1 and CREBBP in Murine Hematopoiesis
Functional Interaction of BRCA1 and CREBBP in Murine Hematopoiesis
复制标题
DOI：
10.1016/j.isci.2019.08.031
复制
发表时间：
2019-09-27
期刊：
影响因子：
5.8
通讯作者：
Ross, Theodora S.
中科院分区：
文献类型：
--
作者：
Holmstrom, Sam R.;Wijayatunge, Ranjula;Ross, Theodora S.
BRCA1和CREBBP都是对造血重要的肿瘤抑制基因。我们以前已经表明，小鼠Brcal是造血干细胞（HSC）的活力所必需的。与导致全血细胞减少的Brcal缺乏相反，我们在此报告Crebbp缺乏导致骨髓增生，与脾脏HSC增加以及致命的全身性炎症性疾病（LD 50 = 86天）相关。为了研究这两种蛋白质在造血中的相互作用，我们产生了双CrebbplBrcal敲除小鼠（DKO）。令我们惊讶的是，与Brcal缺陷小鼠相比，DKO加速了骨髓衰竭，这与更短的寿命有关（LD 50 = 88.5 vs 33天）。此外，Crebbp或Brcal杂合性影响造血表型分别与Brcal或Crebbp完全缺乏。我们还观察到，当CREBBP不存在时，造血组织中BRCA 1蛋白水平较低。总的来说，这些数据表明Crebbp和Brcal在功能上相互作用以维持正常的造血。
Both BRCA1 and CREBBP are tumor suppressor genes that are important for hematopoiesis. We have previously shown that mouse Brcal is essential for hematopoietic stem cell (HSC) viability. In contrast to Brcal deficiency, which results in pancytopenia, we report here that Crebbp deficiency results in myeloproliferation associated with an increase of splenic HSCs as well as a lethal systemic inflammatory disorder (LD50 = 86 days). To investigate the interaction of these two proteins in hematopoiesis, we generated double CrebbplBrcal knockout mice (DKOs). To our surprise, DKOs had accelerated bone marrow failure compared with Brcal-deficient mice and this was associated with an even shorter lifespan (LD50 = 88.5 versus 33 days). Furthermore, Crebbp or Brcal heterozygosity influenced the hematopoietic phenotype associated with complete deficiency of Brcal or Crebbp, respectively. We also observed lower BRCA1 protein levels in hematopoietic tissues when CREBBP is absent. Collectively, these data suggest Crebbp and Brcal functionally interact to maintain normal hematopoiesis.