Calmodulin-dependent protein kinase IV regulates hematopoietic stem cell maintenance
Calmodulin-dependent protein kinase IV regulates hematopoietic stem cell maintenance
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DOI：
10.1074/jbc.m505208200
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发表时间：
2005-09-30
影响因子：
4.8
通讯作者：
Means, AR
中科院分区：
文献类型：
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作者：
Kitsos, CM;Sankar, U;Means, AR
造血干细胞（HSC）产生所有成熟的、终末分化的血液细胞。在这里，我们发现钙调蛋白依赖性蛋白激酶 IV (CaMKIV) 存在于 c-Kit(+) ScaI(+) Lin(-/低) 造血祖细胞 (KLS 细胞) 中，其缺失会导致造血衰竭，其特征是 KLS 细胞群减少，并且这些细胞在连续移植后无法重建血细胞。 CaMKIV 缺失下的 KLS 细胞衰竭与这些细胞在体内和体外的凋亡和增殖增加相关。反过来，这些细胞生物学缺陷与 CREB-丝氨酸 133 磷酸化以及 CREB 结合蛋白 (CBP) 和 Bcl-2 水平的降低相关。在Camk4(-/-) KLS细胞中重新表达CaMKIV可挽救体外增殖缺陷，并将CBP和Bcl-2恢复至野生型水平。这些研究表明 CaMKIV 是 HSC 稳态的调节剂，并表明其作用可能部分是通过 CBP 和 Bcl-2 的调节介导的。
The hematopoietic stem cell (HSC) gives rise to all mature, terminally differentiated cells of the blood. Here we show that calmodulin-dependent protein kinase IV (CaMKIV) is present in c-Kit(+) ScaI(+) Lin(-/low) hematopoietic progenitor cells (KLS cells) and that its absence results in hematopoietic failure, characterized by a diminished KLS cell population and by an inability of these cells to reconstitute blood cells upon serial transplantation. KLS cell failure in the absence of CaMKIV is correlated with increased apoptosis and proliferation of these cells in vivo and in vitro. In turn, these cell biological defects are correlated with decreases in CREB-serine 133 phosphorylation as well as in CREB-binding protein (CBP) and Bcl-2 levels. Re-expression of CaMKIV in Camk4(-/-) KLS cells results in the rescue of the proliferation defects in vitro as well as in the restoration of CBP and Bcl-2 to wild type levels. These studies show that CaMKIV is a regulator of HSC homeostasis and suggest that its effects may be in part mediated via regulation of CBP and Bcl-2.