Deficiency of Rbpj Leads to Defective Stress-Induced Hematopoietic Stem Cell Functions and Hif Mediated Activation of Non-canonical Notch Signaling Pathways.
Deficiency of Rbpj Leads to Defective Stress-Induced Hematopoietic Stem Cell Functions and Hif Mediated Activation of Non-canonical Notch Signaling Pathways.
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DOI：
10.3389/fcell.2020.622190
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发表时间：
2020
影响因子：
5.5
通讯作者：
Rathinam CV
中科院分区：
文献类型：
--
作者：
Lakhan R;Rathinam CV
notch信号的失调与人类病理生物学有关。然而，notch通路在造血中的功能仍不完全清楚。在这里，我们通过基因缺失Rbpj，消除了造血干细胞（hsc）中的典型缺口通路。我们的数据表明，在稳定状态下，正常成人HSC池中缺失标准缺口。然而，在缺乏标准缺口的情况下，HSC对放射、化疗和细胞因子诱导的应激反应的维持和功能受到损害。Rbpj缺失的造血干细胞表现出增殖率下降和p57Kip2表达升高。令人惊讶的是，Rbpj的缺失导致了关键缺口靶基因的上调，以及Hes1与p57和Gata2启动子的结合增强。进一步的分子分析发现，在缺乏Rbpj的情况下，缺口活性增加，Hif蛋白的表达和核易位升高，Hif1α与Hes1启动子的结合增强。这些研究首次确定了非规范notch信号的未知作用，并在造血过程中建立了Hif和notch信号通路之间的功能联系。
Deregulated notch signaling has been associated with human pathobiology. However, functions of notch pathways in hematopoiesis remain incompletely understood. Here, we ablated canonical notch pathways, through genetic deletion of Rbpj, in hematopoietic stem cells (HSCs). Our data identified that loss of canonical notch results in normal adult HSC pool, at steady state conditions. However, HSC maintenance and functions in response to radiation-, chemotherapy-, and cytokine- induced stress were compromised in the absence of canonical notch. Rbpj deficient HSCs exhibit decreased proliferation rates and elevated expression of p57Kip2. Surprisingly, loss of Rbpj resulted in upregulation of key notch target genes and augmented binding of Hes1 to p57 and Gata2 promoters. Further molecular analyses identified an increase in notch activity, elevated expression and nuclear translocation of Hif proteins, and augmented binding of Hif1α to Hes1 promoter in the absence of Rbpj. These studies, for the first time, identify a previously unknown role for non-canonical notch signaling and establish a functional link between Hif and Notch pathways in hematopoiesis.
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DOI：
10.1084/jem.20120993
发表时间：
2013-01-14
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Guiu J;Shimizu R;D'Altri T;Fraser ST;Hatakeyama J;Bresnick EH;Kageyama R;Dzierzak E;Yamamoto M;Espinosa L;Bigas A
通讯作者：
Bigas A
影响因子：
20.3
作者：
Mancini, SJC;Mantei, N;Radtke, F
通讯作者：
Radtke, F
DOI：
10.1084/jem.20062648
发表时间：
2007-07-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Caton ML;Smith-Raska MR;Reizis B
通讯作者：
Reizis B
影响因子：
4.4
作者：
Han, H;Tanigaki, K;Honjo, T
通讯作者：
Honjo, T
影响因子：
23.9
作者：
Mercher T;Cornejo MG;Sears C;Kindler T;Moore SA;Maillard I;Pear WS;Aster JC;Gilliland DG
通讯作者：
Gilliland DG