Role of Geminin in cell fate determination of hematopoietic stem cells (HSCs)
Role of Geminin in cell fate determination of hematopoietic stem cells (HSCs)
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DOI：
10.1007/s12185-016-2060-9
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发表时间：
2016-07
影响因子：
2.1
通讯作者：
S. Yasunaga;Yoshinori Ohno;N. Shirasu;Bo Zhang;Kyoko Suzuki-Takedachi;M. Ohtsubo;Y. Takihara
中科院分区：
文献类型：
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作者：
S. Yasunaga;Yoshinori Ohno;N. Shirasu;Bo Zhang;Kyoko Suzuki-Takedachi;M. Ohtsubo;Y. Takihara
Geminin发挥两种不同的分子作用。Geminin通过与Cdt 1的直接相互作用负调控DNA复制许可，以防止增殖细胞中的再复制。Geminin还通过与Brahma/Brg 1的直接相互作用来调节染色质重塑，以维持干细胞的未分化状态。我们以前发现，Polycomb-group complex 1和Hoxb 4/Hoxa 9是维持造血干细胞（HSC）活性所必需的众所周知的内在因子，它们交替地充当Geminin蛋白的泛素-蛋白酶体系统，以降低蛋白表达水平，并维持HSC活性。因此，推测Geminin在决定细胞命运中起重要作用，即，开启和关闭HSC中的细胞静止和增殖/分化。我们最近产生了重组细胞穿透Geminin（CP-Geminin），使快速纳入和退出Geminin蛋白在细胞中。CP-Geminin可用于调节细胞周期和染色质构型。本文综述了Geminin的分子功能及其表达调控机制，探讨了Geminin在决定HSC细胞命运中的分子作用，并展望了调控HSC和肿瘤干细胞活性的新技术的发展前景。
Geminin exerts two distinct molecular roles. Geminin negatively regulates DNA replication licensing through the direct interaction with Cdt1 to prevent re-replication in proliferating cells. Geminin also regulates chromatin remodeling through the direct interaction with Brahma/Brg1 to maintain undifferentiated states of stem cells. We previously uncovered that Polycomb-group complex 1 and Hoxb4/Hoxa9, well-known intrinsic factors that are essential for maintaining the hematopoietic stem cell (HSC) activity, alternatively act as ubiquitin–proteasome systems for Geminin protein to reduce the protein expression level, and sustain the HSC activity. Thus, Geminin is presumed to play an important role in determining cell fate, i.e., turning on and off cellular quiescence and proliferation/differentiation, in HSCs. We recently generated recombinant cell-penetrating Geminin (CP-Geminin), enabling rapid incorporation and withdraw of Geminin protein in cells. CP-Geminin may be useful in regulating the cell cycle and chromatin configuration. In this article, we summarize current information on the molecular functions of Geminin and the regulatory system for Geminin protein expression, and argue for the molecular role of Geminin in cell fate determination of HSCs, and future perspective of a new technology for manipulating the activities of HSCs and cancer stem cells (CSCs).