Ribosomal protein L11 mutation in zebrafish leads to haematopoietic and metabolic defects.
Ribosomal protein L11 mutation in zebrafish leads to haematopoietic and metabolic defects.
复制标题
DOI：
10.1111/j.1365-2141.2010.08396.x
复制
发表时间：
2011-01
影响因子：
6.5
通讯作者：
Lin S
中科院分区：
文献类型：
--
作者：
Danilova N;Sakamoto KM;Lin S
核糖体蛋白的突变与一种先天性综合征--钻石-黑范氏贫血(DBA)有关，表现为红细胞再生障碍、发育异常和恶性风险增加。最近的研究表明P53的激活参与了DBA的发生。然而，目前还不清楚哪些途径参与了DBA的表型，以及它们是如何影响DBA表型的。在这里，我们发现rpl11基因的斑马鱼突变体在造血干细胞(HSCs)的发育和红系细胞的维持方面都存在缺陷。突变体的分子特征包括P53靶基因上调和代谢的全球变化。一些途径的改变可能影响造血，包括促凋亡和细胞周期停滞基因的上调，糖酵解的抑制，生物合成的下调和细胞骨架的失调。这些途径中的每一条都单独与血液疾病有关。抑制P53基因可部分挽救突变体的造血功能。总之，我们认为DBA的独特表型是由P53蛋白家族和非P53蛋白家族介导的几条异常调节的分子通路的总和，这些分子通路对DBA的血液学和其他细胞通路具有协同影响。我们的结果为DBA的发病机制提供了新的见解，并指出了治疗干预的潜在途径。
Mutations in ribosomal proteins are associated with a congenital syndrome, Diamond–Blackfan anaemia (DBA), manifested by red blood cell aplasia, developmental abnormalities and increased risk of malignancy. Recent studies suggest the involvement of p53 activation in DBA. However, which pathways are involved and how they contribute to the DBA phenotype remains unknown. Here we show that a zebrafish mutant for the rpl11 gene had defects both in the development of haematopoietic stem cells (HSCs) and maintenance of erythroid cells. The molecular signature of the mutant included upregulation of p53 target genes and global changes in metabolism. The changes in several pathways may affect haematopoiesis including upregulation of pro-apoptotic and cell cycle arrest genes, suppression of glycolysis, downregulation of biosynthesis and dysregulation of cytoskeleton. Each of these pathways has been individually implicated in haematological diseases. Inhibition of p53 partially rescued haematopoiesis in the mutant. Altogether, we propose that the unique phenotype of DBA is a sum of several abnormally regulated molecular pathways, mediated by the p53 protein family and p53-independent, which have synergistic impact on haematological and other cellular pathways affected in DBA. Our results provide new insights into the pathogenesis of DBA and point to the potential avenues for therapeutic intervention.
登录
查看更多内容
影响因子：
4.4
作者：
Avondo F;Roncaglia P;Crescenzio N;Krmac H;Garelli E;Armiraglio M;Castagnoli C;Campagnoli MF;Ramenghi U;Gustincich S;Santoro C;Dianzani I
通讯作者：
Dianzani I
影响因子：
20.3
作者：
Ebert, BL;Lee, MM;Sieff, CA
通讯作者：
Sieff, CA
影响因子：
20.3
作者：
Flygare, Johan;Aspesi, Anna;Ellis, Steven R.
通讯作者：
Ellis, Steven R.
影响因子：
64.8
作者：
Ebert, Benjamin L.;Pretz, Jennifer;Bosco, Jocelyn;Chang, Cindy Y.;Tamayo, Pablo;Galili, Naomi;Raza, Azra;Root, David E.;Attar, Eyal;Ellis, Steven R.;Golub, Todd R.
通讯作者：
Golub, Todd R.
影响因子：
5.2
作者：
Gazda, Hanna T.;Kho, Alvin T.;Beggs, Alan H.
通讯作者：
Beggs, Alan H.