Functional impact of Aurora A-mediated phosphorylation of HP1γ at serine 83 during cell cycle progression.
Functional impact of Aurora A-mediated phosphorylation of HP1γ at serine 83 during cell cycle progression.
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DOI：
10.1186/1756-8935-6-21
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发表时间：
2013-07-05
影响因子：
3.9
通讯作者：
Lomberk G
中科院分区：
文献类型：
--
作者：
Grzenda A;Leonard P;Seo S;Mathison AJ;Urrutia G;Calvo E;Iovanna J;Urrutia R;Lomberk G
先前在裂殖酵母裂殖酵母中进行的优雅研究已经确定了纺锤体极形成和适当细胞分裂需要异染色质蛋白 1 (HP1)。在哺乳动物细胞中，HP1γ 与体细胞和生殖细胞增殖有关。高水平的 HP1γ 蛋白与细胞增殖和肿瘤发生增强相关，而其基因失活会导致减数分裂和有丝分裂失败。然而，对于支持有丝分裂进展至关重要的激酶对 HP1γ 的调节仍有待充分表征。我们首次报道，在有丝分裂细胞分裂过程中，HP1γ 在 G2/M 期的丝氨酸 83 (Ser83) 处共定位并被 Aurora A 磷酸化。由于 Aurora A 调节细胞增殖和有丝分裂畸变，我们使用 siRNA 介导的敲低以及拟磷酸化和非磷酸化评估 HP1γ 在调节这些现象中的作用 定点突变体。我们发现 HP1γ 的遗传下调会降低 HP1γ Ser83 (P-Ser83-HP1γ) 磷酸化水平，导致有丝分裂畸变，可以通过重新引入野生型 HP1γ 来挽救这种畸变，但不能通过重新引入不可磷酸化的 S83A-HP1γ 突变体来挽救这种畸变。此外，增殖测定表明，磷酸化S83D-HP1γ增加了5-乙炔基-2'-脱氧尿苷（EdU）的掺入，而不可磷酸化的S83A-HP1γ突变体消除了这种效应。全基因组表达谱显示，这些突变体对有丝分裂功能的影响以模仿 P-Ser83-HP1γ 开启和关闭状态的方式一致地反映在 G2/M 基因表达网络中。这是对有丝分裂 A-HP1γ 通路的首次描述，该通路的完整性对于执行适当的体细胞分裂是必要的，提供了对与这种重要染色质蛋白的不同功能结果相关的特定类型的翻译后修饰的深入了解。
Previous elegant studies performed in the fission yeast Schizosaccharomyces pombe have identified a requirement for heterochromatin protein 1 (HP1) for spindle pole formation and appropriate cell division. In mammalian cells, HP1γ has been implicated in both somatic and germ cell proliferation. High levels of HP1γ protein associate with enhanced cell proliferation and oncogenesis, while its genetic inactivation results in meiotic and mitotic failure. However, the regulation of HP1γ by kinases, critical for supporting mitotic progression, remains to be fully characterized. We report for the first time that during mitotic cell division, HP1γ colocalizes and is phosphorylated at serine 83 (Ser83) in G2/M phase by Aurora A. Since Aurora A regulates both cell proliferation and mitotic aberrations, we evaluated the role of HP1γ in the regulation of these phenomena using siRNA-mediated knockdown, as well as phosphomimetic and nonphosphorylatable site-directed mutants. We found that genetic downregulation of HP1γ, which decreases the levels of phosphorylation of HP1γ at Ser83 (P-Ser83-HP1γ), results in mitotic aberrations that can be rescued by reintroducing wild type HP1γ, but not the nonphosphorylatable S83A-HP1γ mutant. In addition, proliferation assays showed that the phosphomimetic S83D-HP1γ increases 5-ethynyl-2´-deoxyuridine (EdU) incorporation, whereas the nonphosphorylatable S83A-HP1γ mutant abrogates this effect. Genome-wide expression profiling revealed that the effects of these mutants on mitotic functions are congruently reflected in G2/M gene expression networks in a manner that mimics the on and off states for P-Ser83-HP1γ. This is the first description of a mitotic Aurora A-HP1γ pathway, whose integrity is necessary for the execution of proper somatic cell division, providing insight into specific types of posttranslational modifications that associate to distinct functional outcomes of this important chromatin protein.
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DOI：
10.1111/j.1432-1033.1997.t01-2-00527.x
发表时间：
1997-01-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Meijer, L;Borgne, A;Moulinoux, JP
通讯作者：
Moulinoux, JP
影响因子：
3.7
作者：
Kondo Y;Shen L;Ahmed S;Boumber Y;Sekido Y;Haddad BR;Issa JP
通讯作者：
Issa JP
影响因子：
21.3
作者：
Lomberk, G;Bensi, D;Urrutia, R
通讯作者：
Urrutia, R
影响因子：
5.3
作者：
Gebelein, B;Urrutia, R
通讯作者：
Urrutia, R
影响因子：
--
作者：
Kaller, M;Euteneuer, U;Nellen, W
通讯作者：
Nellen, W