Role of the HCF-1 Basic Region in Sustaining Cell Proliferation
Role of the HCF-1 Basic Region in Sustaining Cell Proliferation
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DOI：
10.1371/journal.pone.0009020
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发表时间：
2010-02-02
期刊：
影响因子：
3.7
通讯作者：
Herr, Winship
中科院分区：
文献类型：
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作者：
Mangone, Marco;Myers, Michael P.;Herr, Winship
背景：人类单纯疱疹病毒相关宿主细胞因子1(HCF-1)是一种保守的人类转录共调节因子，它将阳性和阴性的组蛋白修饰活性与序列特异的DNA结合转录因子联系起来。它被合成为一个2035年的氨基酸前体，被切割后产生一个氨基(HCF-1(N))末端亚基和一个羧基(HCF-1(C))末端亚基，前者促进G1期到S期的进程，后者控制M期细胞分裂的多个方面。HCF-1(N)亚基包含一个Kelch结构域，它将HCF-1与序列特异的DNA结合转录因子捆绑在一起，以及一个特征不佳的所谓“碱性”区域(由于碱性氨基酸与酸性氨基酸的高比例)，该区域是细胞增殖所必需的，已被证明与Sin3组蛋白脱乙酰基酶(HDAC)成分有关。在这里，我们研究了碱性区域在细胞增殖和G1到S相变分析中的作用。方法/主要发现：令人惊讶的是，与序列特异性转录因子的转录激活域非常相似，在促进细胞增殖或G1到S相变所需的碱性区域内没有唯一的序列。事实上，促进这些活动的能力取决于大小，因此基本区域部分越短，观察到的活动就越少。然而，我们发现，在温度敏感的tsBN67细胞实验中，促进细胞增殖的基本区域要求比HCF-1siRNA耗竭HeLa细胞实验中从G1期到S期的进展更严格。因此，在这些检测中，仅碱性区域的任何一半都可以支持从G1期到S期的进展，但不能有效地支持细胞增殖。然而，基本区域显示出相当大的结构可塑性，因为当每一半串联复制时，每一半都能够促进细胞增殖。与促进细胞周期进程的潜在作用一致，Sin3a HDAC成分可以独立地与融合到HCF-1 Kelch结构域的碱性区域的任何一半结合。结论/意义：在保守的情况下，HCF-1碱性区域在控制细胞增殖方面表现出显著的结构灵活性。
Background: The human herpes simplex virus-associated host cell factor 1 (HCF-1) is a conserved human transcriptional coregulator that links positive and negative histone modifying activities with sequence-specific DNA-binding transcription factors. It is synthesized as a 2035 amino acid precursor that is cleaved to generate an amino- (HCF-1(N)) terminal subunit, which promotes G1-to-S phase progression, and a carboxy- (HCF-1(C)) terminal subunit, which controls multiple aspects of cell division during M phase. The HCF-1(N) subunit contains a Kelch domain that tethers HCF-1 to sequence-specific DNA-binding transcription factors, and a poorly characterized so called "Basic'' region (owing to a high ratio of basic vs. acidic amino acids) that is required for cell proliferation and has been shown to associate with the Sin3 histone deacetylase (HDAC) component. Here we studied the role of the Basic region in cell proliferation and G1-to-S phase transition assays.Methodology/Principal Findings: Surprisingly, much like the transcriptional activation domains of sequence-specific DNA-binding transcription factors, there is no unique sequence within the Basic region required for promoting cell proliferation or G1-to-S phase transition. Indeed, the ability to promote these activities is size dependent such that the shorter the Basic region segment the less activity observed. We find, however, that the Basic region requirements for promoting cell proliferation in a temperature-sensitive tsBN67 cell assay are more stringent than for G1-to-S phase progression in an HCF-1 siRNA-depletion HeLa-cell assay. Thus, either half of the Basic region alone can support G1-to-S phase progression but not cell proliferation effectively in these assays. Nevertheless, the Basic region displays considerable structural plasticity because each half is able to promote cell proliferation when duplicated in tandem. Consistent with a potential role in promoting cell-cycle progression, the Sin3a HDAC component can associate independently with either half of the Basic region fused to the HCF-1 Kelch domain.Conclusions/Significance: While conserved, the HCF-1 Basic region displays striking structural flexibility for controlling cell proliferation.