CENP-A Phosphorylation by Aurora-A in Prophase Is Required for Enrichment of Aurora-B at Inner Centromeres and for Kinetochore Function

Kunitoku, Naoko; Sasayama, Takashi; Marumoto, Tomotoshi; Zhang, Dongwei; Honda, Shoji; Kobayashi, Osamu; Hatakeyama, Katsuyoshi; Ushio, Yukitaka; Saya, Hideyuki; Hirota, Toru

doi:10.1016/s1534-5807(03)00364-2

Cited by 215 publications

(201 citation statements)

References 33 publications

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“…The histone H3 variant CENP-A that defines the centromere (Earnshaw and Rothfield, 1985;Howman et al, 2000;Yoda et al, 2000) has been implicated in this process. A recent study reported that human CENP-A phosphorylated by Aurora A at serine 7 is required to restrict Aurora B to the centromere (Kunitoku et al, 2003). In chicken DT-40 cells and C. elegans embryos, however, CENP-A seems to be dispensable for the localization of INCENP (Oegema et al, 2001;Regnier et al, 2005).…”

Section: Cpc Loading Onto the Centromere Is Independent Of Cenp-a Andmentioning

confidence: 99%

Centromere Targeting of the Chromosomal Passenger Complex Requires a Ternary Subcomplex of Borealin, Survivin, and the N-Terminal Domain of INCENP

Klein

Nigg

Grüneberg

2006

MBoC

164

170

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The chromosomal passenger complex (CPC), consisting of the serine/threonine kinase Aurora B, the inner centromere protein INCENP, Survivin, and Borealin/DasraB, has essential functions at the centromere in ensuring correct chromosome alignment and segregation. Despite observations that small interfering RNA-mediated knockdown of any one member of the CPC abolishes localization of the other subunits, it remains unclear how the complex is targeted to the centromere. We have now identified a ternary subcomplex of the CPC comprising Survivin, Borealin, and the N-terminal 58 amino acids of INCENP in vitro and in vivo. This subcomplex was found to be essential and sufficient for targeting to the centromere. Notably, Aurora B kinase, the enzymatic core of the CPC, was not required for centromere localization of the subcomplex. We demonstrate that CPC targeting to the centromere does not depend on CENP-A and hMis12, two core components for kinetochore/centromere assembly, and provide evidence that the CPC may be directed to centromeric DNA directly via the Borealin subunit. Our findings thus establish a functional module within the CPC that assembles on the N terminus of INCENP and controls centromere recruitment.

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Section: Cpc Loading Onto the Centromere Is Independent Of Cenp-a Andmentioning

confidence: 99%

Centromere Targeting of the Chromosomal Passenger Complex Requires a Ternary Subcomplex of Borealin, Survivin, and the N-Terminal Domain of INCENP

Klein

Nigg

Grüneberg

2006

MBoC

164

170

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“…Interestingly, (i) small molecule-mediated inhibition of Aurora A by MLN8054 or Aurora A depletion (Huck et al), (ii) knockdown of TACC3 (this study), and (iii) reduction of the centromeric protein CENP-A (Maehara et al), all trigger a comparable premature senescence response preventing propagation of defective mitoses. CENP-A itself is regulated by phosphorylation in a cell cycle-dependent manner through both Aurora A in prophase and Aurora B in metaphase (Kunitoku et al, 2003).…”

Section: Downregulation Of Tacc3 Induces Cellular Senescence S Schmidmentioning

confidence: 99%

The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

et al. 2010

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Microtubule-interfering cancer drugs such as paclitaxel (PTX) often cause chemoresistance and severe side effects, including neurotoxicity. To explore potentially novel antineoplastic molecular targets, we investigated the cellular response of breast carcinoma cells to short hairpin(sh)RNA-mediated depletion of the centrosomal protein transforming acidic coiled coil (TACC) 3, an Aurora A kinase target expressed during mitosis. Unlike PTX, knockdown of TACC3 did not trigger a cell death response, but instead resulted in a progressive loss of the pro-apoptotic Bcl-2 protein Bim that links microtubule integrity to spindle poison-induced cell death. Interestingly, TACC3-depleted cells arrested in G 1 through a cellular senescence program characterized by the upregulation of nuclear p21 WAF , downregulation of the retinoblastoma protein and extracellular signal-regulated kinase 1/2, formation of HP1c (phospho-Ser83)-positive senescence-associated heterochromatic foci and increased senescence-associated b-galactosidase activity. Remarkably, the onset of senescence following TACC3 knockdown was strongly accelerated in the presence of non-toxic PTX concentrations. Thus, we conclude that mitotic spindle stress is a major trigger of premature senescence and propose that the combined targeting of the centrosomal Aurora A-TACC3 axis together with drugs interfering with microtubule dynamics may efficiently improve the chemosensitivity of cancer cells.

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“…Dysfunction of some mitotic kinases leads to chromosome rearrangements and aneuploidy, which are hallmarks of many human cancers, indicating that mitotic kinases are important for maintaining genomic integrity (Nigg, 2001). Aurora A serine/threonine mitotic kinase has crucial roles in various mitotic events such as centrosome maturation and separation, mitotic entry, bipolar spindle assembly, chromosome alignment and cytokinesis (Meraldi et al, 2002;Hirota et al, 2003;Kunitoku et al, 2003;Marumoto et al, 2003Marumoto et al, , 2005Giet et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Aurora A overexpression induces cellular senescence in mammary gland hyperplastic tumors developed in p53-deficient mice

et al. 2008

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Aurora A mitotic kinase is frequently overexpressed in various human cancers and is widely considered to be an oncoprotein. However, the cellular contexts in which Aurora A induces malignancy in vivo are still unclear. We previously reported a mouse model in which overexpression of human Aurora A in the mammary gland leads to small hyperplastic changes but not malignancy because of the induction of p53-dependent apoptosis. To study the additional factors required for Aurora A-associated tumorigenesis, we generated a new Aurora A overexpression mouse model that lacks p53. We present evidence here that Aurora A overexpression in primary mouse embryonic fibroblasts (MEFs) that lack p53 overrides postmitotic checkpoint and leads to the formation of multinucleated polyploid cells. Induction of Aurora A overexpression in the mammary glands of p53-deficient mice resulted in development of precancerous lesions that were histologically similar to atypical ductal hyperplasia in human mammary tissue and showed increased cellular senescence and p16 expression. We further observed DNA damage in p53-deficient primary MEFs after Aurora A overexpression. Our results suggest that Aurora A overexpression in mammary glands is insufficient for the development of malignant tumors in p53-deficient mice because of the induction of cellular senescence. Both p53 and p16 are critical in preventing mammary gland tumorigenesis in the Aurora A overexpression mouse model.

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CENP-A Phosphorylation by Aurora-A in Prophase Is Required for Enrichment of Aurora-B at Inner Centromeres and for Kinetochore Function

Cited by 215 publications

References 33 publications

Centromere Targeting of the Chromosomal Passenger Complex Requires a Ternary Subcomplex of Borealin, Survivin, and the N-Terminal Domain of INCENP

Centromere Targeting of the Chromosomal Passenger Complex Requires a Ternary Subcomplex of Borealin, Survivin, and the N-Terminal Domain of INCENP

The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

Aurora A overexpression induces cellular senescence in mammary gland hyperplastic tumors developed in p53-deficient mice

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