Dataset Information

Aurora-B/AIM-1 regulates the dynamic behavior of HP1alpha at the G2-M transition.

ABSTRACT: Heterochromatin protein 1 (HP1) plays an important role in heterochromatin formation and undergoes large-scale, progressive dissociation from heterochromatin in prophase cells. However, the mechanisms regulating the dynamic behavior of HP1 are poorly understood. In this study, the role of Aurora-B was investigated with respect to the dynamic behavior of HP1alpha. Mammalian Aurora-B, AIM-1, colocalizes with HP1alpha to the heterochromatin in G2. Depletion of Aurora-B/AIM-1 inhibited dissociation of HP1alpha from the chromosome arms at the G2-M transition. In addition, depletion of INCENP led to aberrant cellular localization of Aurora-B/AIM-1, but it did not affect heterochromatin targeting of HP1alpha. It was proposed in the binary switch hypothesis that phosphorylation of histone H3 at Ser-10 negatively regulates the binding of HP1alpha to the adjacent methylated Lys-9. However, Aurora-B/AIM-1-mediated phosphorylation of H3 induced dissociation of the HP1alpha chromodomain but not of the intact protein in vitro, indicating that the center and/or C-terminal domain of HP1alpha interferes with the effect of H3 phosphorylation on HP1alpha dissociation. Interestingly, Lys-9 methyltransferase SUV39H1 is abnormally localized together along the metaphase chromosome arms in Aurora-B/AIM-1-depleted cells. In conclusion, these results showed that Aurora-B/AIM-1 is necessary for regulated histone modifications involved in binding of HP1alpha by the N terminus of histone H3 during mitosis.

SUBMITTER: Terada Y

PROVIDER: S-EPMC1483052 | biostudies-literature | 2006 Jul

REPOSITORIES: biostudies-literature

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Aurora-B/AIM-1 regulates the dynamic behavior of HP1alpha at the G2-M transition.

Terada Yasuhiko Y

Molecular biology of the cell 20060510 7

Heterochromatin protein 1 (HP1) plays an important role in heterochromatin formation and undergoes large-scale, progressive dissociation from heterochromatin in prophase cells. However, the mechanisms regulating the dynamic behavior of HP1 are poorly understood. In this study, the role of Aurora-B was investigated with respect to the dynamic behavior of HP1alpha. Mammalian Aurora-B, AIM-1, colocalizes with HP1alpha to the heterochromatin in G2. Depletion of Aurora-B/AIM-1 inhibited dissociation ...[more]

PMID: 16687578

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Project description:Cell cycle dysregulation leads to uncontrolled cell proliferation and tumorigenesis. Understanding the molecular mechanisms underlying cell cycle progression can provide clues leading to the identification of key proteins involved in cancer development. In this study, we performed proteomics analysis to identify novel regulators of the cell cycle. We found that potassium channel tetramerization domain containing 12 (KCTD12) was significantly upregulated in M phase compared with S phase. We also found that KCTD12 overexpression not only facilitated the G2/M transition and induced cancer cell proliferation, but also promoted the growth of subcutaneous tumors and Ki-67 proliferation index in mice. Regarding the mechanism underlying these phenomena, cyclin-dependent kinase 1 (CDK1) was identified as an interacting partner of KCTD12 by immunoprecipitation and mass spectrometry analysis, which showed that KCTD12 activated CDK1 and Aurora kinase A (Aurora A) and that the effects of KCTD12 on CDK1 phosphorylation and cell proliferation were abrogated by cell division cycle 25B (CDC25B) silencing. In addition, Aurora A phosphorylated KCTD12 at serine 243, thereby initiating a positive feedback loop necessary for KCTD12 to exert its cancer-promoting effects. Furthermore, we analyzed the expression levels of various genes and the correlations between the expression of these genes and survival using tumor tissue microarray and Gene Expression Omnibus (GEO) data sets. The data showed that KCTD12 expression was significantly upregulated in cervical and lung cancers. More importantly, high KCTD12 expression was associated with larger tumor sizes, higher pathological stages and poor patient survival. Collectively, our study demonstrate that KCTD12 binds to CDC25B and activates CDK1 and Aurora A to facilitate the G2/M transition and promote tumorigenesis and that Aurora A phosphorylates KCTD12 at serine 243 to trigger a positive feedback loop, thereby potentiating the effects of KCTD12. Thus, the KCTD12-CDC25B-CDK1-Aurora A axis has important implications for cancer diagnoses and prognoses.

Dataset Information

Aurora-B/AIM-1 regulates the dynamic behavior of HP1alpha at the G2-M transition.

Publications

Aurora-B/AIM-1 regulates the dynamic behavior of HP1alpha at the G2-M transition.

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