期刊
EPIGENETICS & CHROMATIN
卷 6, 期 -, 页码 -出版社
BMC
DOI: 10.1186/1756-8935-6-21
关键词
Heterochromatin protein 1 (HP1); Mitosis; Aurora kinase; Epigenetics; Spindle pole; Centrosome
资金
- Career Development Award from the Mayo Clinic SPORE in Pancreatic Cancer [P50 CA102701]
- National Institutes of Health [DK52913, T32CA148073]
- Mayo Clinic Center for Cell Signaling in Gastroenterology [P30DK084567]
- Mayo Foundation
- Fraternal Order of Eagles
Background: 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, HP1 gamma has been implicated in both somatic and germ cell proliferation. High levels of HP1 gamma protein associate with enhanced cell proliferation and oncogenesis, while its genetic inactivation results in meiotic and mitotic failure. However, the regulation of HP1 gamma by kinases, critical for supporting mitotic progression, remains to be fully characterized. Results: We report for the first time that during mitotic cell division, HP1 gamma colocalizes and is phosphorylated at serine 83 (Ser(83)) in G(2)/M phase by Aurora A. Since Aurora A regulates both cell proliferation and mitotic aberrations, we evaluated the role of HP1 gamma 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 HP1 gamma, which decreases the levels of phosphorylation of HP1 gamma at Ser83 (P-Ser(83)-HP1 gamma), results in mitotic aberrations that can be rescued by reintroducing wild type HP1 gamma, but not the nonphosphorylatable S83A-HP1 gamma mutant. In addition, proliferation assays showed that the phosphomimetic S83D-HP1 gamma increases 5-ethynyl-2'-deoxyuridine (EdU) incorporation, whereas the nonphosphorylatable S83A-HP1 gamma mutant abrogates this effect. Genome-wide expression profiling revealed that the effects of these mutants on mitotic functions are congruently reflected in G(2)/M gene expression networks in a manner that mimics the on and off states for P-Ser(83)-HP1 gamma. Conclusions: This is the first description of a mitotic Aurora A-HP1 gamma 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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