Requirements for survivin in terminal differentiation of erythroid cells and maintenance of hematopoietic stem and progenitor cells.
Requirements for survivin in terminal differentiation of erythroid cells and maintenance of hematopoietic stem and progenitor cells.
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DOI：
10.1084/jem.20062395
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发表时间：
2007-07-09
期刊：
影响因子：
--
通讯作者：
Crispino JD
中科院分区：
文献类型：
--
作者：
Leung CG;Xu Y;Mularski B;Liu H;Gurbuxani S;Crispino JD
Survivin是凋亡抑制蛋白（inhibitor of apoptosis protein，IAP）家族中最小的成员，是一种染色体过客蛋白，介导纺锤体组装检查点和胞质分裂，也是一种凋亡抑制因子。生存素在人类癌症中经常过度表达，而在大多数成人组织中不表达，已被提出作为抗癌治疗的有吸引力的靶点，在某些情况下，甚至被吹捧为癌症特异性基因。然而，存活素在增殖的成体细胞中表达，包括人造血干细胞、T淋巴细胞和红系细胞在其整个成熟过程中。因此，目前尚不清楚生存素靶向抗癌疗法如何影响稳态血液发育。为了解决这个问题，我们使用了一种条件基因靶向策略，并消除了小鼠造血区室中生存素的表达。我们发现，生存素的诱导性缺失导致骨髓消融，广泛的造血祖细胞和快速死亡的损失。令人惊讶的是，生存素的杂合缺失导致动物亚组中红细胞生成缺陷，去核红细胞急剧减少，并存在未成熟的巨幼红细胞。我们的研究表明，生存素是必不可少的稳态造血和成人的生存，并进一步，高水平的生存素表达是正确的红细胞分化的关键。
Survivin, which is the smallest member of the inhibitor of apoptosis protein (IAP) family, is a chromosomal passenger protein that mediates the spindle assembly checkpoint and cytokinesis, and also functions as an inhibitor of apoptosis. Frequently overexpressed in human cancers and not expressed in most adult tissues, survivin has been proposed as an attractive target for anticancer therapies and, in some cases, has even been touted as a cancer-specific gene. Survivin is, however, expressed in proliferating adult cells, including human hematopoietic stem cells, T-lymphocytes, and erythroid cells throughout their maturation. Therefore, it is unclear how survivin-targeted anticancer therapies would impact steady-state blood development. To address this question, we used a conditional gene-targeting strategy and abolished survivin expression from the hematopoietic compartment of mice. We show that inducible deletion of survivin leads to ablation of the bone marrow, with widespread loss of hematopoietic progenitors and rapid mortality. Surprisingly, heterozygous deletion of survivin causes defects in erythropoiesis in a subset of the animals, with a dramatic reduction in enucleated erythrocytes and the presence of immature megaloblastic erythroblasts. Our studies demonstrate that survivin is essential for steady-state hematopoiesis and survival of the adult, and further, that a high level of survivin expression is critical for proper erythroid differentiation.
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DOI：
10.1083/jcb.105.5.2053
发表时间：
1987-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Cooke CA;Heck MM;Earnshaw WC
通讯作者：
Earnshaw WC
影响因子：
4.8
作者：
Dohi, T;Okada, K;Altieri, DC
通讯作者：
Altieri, DC
影响因子：
9.2
作者：
Fraser, AG;James, C;Hengartner, MO
通讯作者：
Hengartner, MO
影响因子：
19
作者：
Adams, RR;Carmena, M;Earnshaw, WC
通讯作者：
Earnshaw, WC
DOI：
10.1073/pnas.0500303102
发表时间：
2005-08-09
影响因子：
11.1
作者：
Gurbuxani, S;Xu, YF;Crispino, JD
通讯作者：
Crispino, JD