Functional Interaction of BRCA1 and CREBBP in Murine Hematopoiesis

被引：6

作者：

Holmstrom, Sam R. ^{[1
]}

Wijayatunge, Ranjula ^{[1
]}

McCrum, Kelly ^{[1
]}

Mgbemena, Victoria E. ^{[1
]}

Ross, Theodora S. ^{[1
]}

机构：

[1] Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, ND3-214,5323 Harry Hines Blvd, Dallas, TX 75390 USA

来源：

ISCIENCE | 2019年 / 19卷

关键词：

TRANSCRIPTIONAL COACTIVATORS; BINDING-PROTEIN; STEM-CELLS; P300; MICE; CBP; EXPRESSION; BREAST; CANCER; PROGENITOR;

D O I：

10.1016/j.isci.2019.08.031

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：809 / +

页数：24

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