Developmental enhancement of adenylate kinase-AMPK metabolic signaling axis supports stem cell cardiac differentiation.
Developmental enhancement of adenylate kinase-AMPK metabolic signaling axis supports stem cell cardiac differentiation.
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DOI：
10.1371/journal.pone.0019300
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发表时间：
2011-04-27
期刊：
影响因子：
3.7
通讯作者：
Terzic A
中科院分区：
文献类型：
--
作者：
Dzeja PP;Chung S;Faustino RS;Behfar A;Terzic A
协调细胞分化的能量和代谢回路在很大程度上是未知的。腺苷酸激酶 (AK) 和相关的 AMP 激活蛋白激酶 (AMPK) 构成了主要的代谢信号轴，但该系统在指导分化和谱系规范中的作用仍不清楚。心脏干细胞分化是器官发生中最早的事件，也是发育生物能学的合适模型。心脏发生过程中胚胎干细胞的分子分析揭示了编码 AK-AMP-AMPK 代谢监视轴的腺苷酸激酶和 AMPK 基因的独特表达模式。心脏分化上调胞质 AK1 亚型，使 AMP 生成腺苷酸激酶活性加倍，并增加 AMP/ATP 比率。在细胞周期开始时，AK1 易位到细胞核中，并在能量消耗中期与着丝粒相关。与此同时，心脏 AMP 信号受体 AMPKα2 上调并作为具有信号传导能力的磷酸化 p-AMPKα(Thr172) 重新分布到核区室。心肌生长因子 TGF-β 促进 AK1 表达，而用 siRNA 敲低 AK1、AK2 和 AK5 活性或通过高血糖抑制会破坏心脏发生，从而损害线粒体和肌原纤维网络的形成和收缩性能。肌酸激酶（另一种磷酸转移途径）的诱导可补偿腺苷酸激酶依赖性能量缺陷。腺苷酸激酶/AMPK串联的发育部署和上调为干细胞心脏分化的执行提供了核胞质能量和代谢信号传导载体。与细胞周期和不对称细胞分裂相关的腺苷酸激酶-AMPK 回路的靶向重新分布揭示了心脏发生和心脏组织再生的调节因子。
Energetic and metabolic circuits that orchestrate cell differentiation are largely unknown. Adenylate kinase (AK) and associated AMP-activated protein kinase (AMPK) constitute a major metabolic signaling axis, yet the role of this system in guiding differentiation and lineage specification remains undefined. Cardiac stem cell differentiation is the earliest event in organogenesis, and a suitable model of developmental bioenergetics. Molecular profiling of embryonic stem cells during cardiogenesis revealed here a distinct expression pattern of adenylate kinase and AMPK genes that encode the AK-AMP-AMPK metabolic surveillance axis. Cardiac differentiation upregulated cytosolic AK1 isoform, doubled AMP-generating adenylate kinase activity, and increased AMP/ATP ratio. At cell cycle initiation, AK1 translocated into the nucleus and associated with centromeres during energy-consuming metaphase. Concomitantly, the cardiac AMP-signal receptor AMPKα2 was upregulated and redistributed to the nuclear compartment as signaling-competent phosphorylated p-AMPKα(Thr172). The cardiogenic growth factor TGF-β promoted AK1 expression, while knockdown of AK1, AK2 and AK5 activities with siRNA or suppression by hyperglycemia disrupted cardiogenesis compromising mitochondrial and myofibrillar network formation and contractile performance. Induction of creatine kinase, the alternate phosphotransfer pathway, compensated for adenylate kinase-dependent energetic deficits. Developmental deployment and upregulation of the adenylate kinase/AMPK tandem provides a nucleocytosolic energetic and metabolic signaling vector integral to execution of stem cell cardiac differentiation. Targeted redistribution of the adenylate kinase-AMPK circuit associated with cell cycle and asymmetric cell division uncovers a regulator for cardiogenesis and heart tissue regeneration.
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影响因子：
3.7
作者：
Chiriac A;Nelson TJ;Faustino RS;Behfar A;Terzic A
通讯作者：
Terzic A
影响因子：
5
作者：
Chung S;Arrell DK;Faustino RS;Terzic A;Dzeja PP
通讯作者：
Dzeja PP
影响因子：
5.2
作者：
Arrell, D. Kent;Niederlaender, Nicolas J.;Terzic, Andre
通讯作者：
Terzic, Andre
影响因子：
4.8
作者：
Burkart, Alison;Shi, Xiarong;Corvera, Silvia
通讯作者：
Corvera, Silvia
DOI：
10.1016/j.cbpb.2009.01.006
发表时间：
2009-05-01
影响因子：
2.2
作者：
Fujisawa, Koichi;Murakami, Ryutaro;Noma, Takafumi
通讯作者：
Noma, Takafumi