Cell Cycle-dependent Expression and Spindle Pole Localization of a Novel Human Protein Kinase, Aik, Related to Aurora of Drosophila and Yeast Ipl1

Kimura, Masashi; Kotani, Shunsuke; Hattori, Takayuki; Sumi, Noriko; Yoshioka, Takashi; Todokoro, Kazuo; Okano, Yukio

doi:10.1074/jbc.272.21.13766

Cited by 239 publications

(232 citation statements)

References 33 publications

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“…[1][2][3][4] It has been shown by in vitro study using NIH-3T3 cells that over-expression of STK15/BTAK induces amplification of centrosomes. 4 Since the centrosomes play an essential role in chromosomal segregation during cell division through establishment of bipolar spindles, their amplification leads to chromosomal instability (CIN).…”

Section: Abstract: Stk15/btak; Real-time Rt-pcr; Chromosomal Instabimentioning

confidence: 99%

Association of centrosomal kinaseSTK15/BTAK mRNA expression with chromosomal instability in human breast cancers

et al. 2001

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Over-expression of a centrosomal serine/threonine kinase, STK15/BTAK, induces centrosome amplification, which results in chromosomal instability (CIN) in cell culture. In the present study, we investigated the correlation of STK15/BTAK mRNA expression with CIN and various clinicopathological factors in human breast cancer. STK15/BTAK mRNA levels were quantified by real-time PCR, and CIN values were determined by FISH analysis of chromosomes 1, 11 and 17 using centromeric probes. STK15/BTAK mRNA levels (0.310 ؎ 0.413, mean ؎ SD, n ‫؍‬ 47) in breast cancers were significantly (p < 0.01) higher than those in normal breast tissues (0.044 ؎ 0.029, n ‫؍‬ 9). Furthermore, breast cancers were divided into 3 groups (low, intermediate and high) according to STK15/BTAK mRNA expression levels. CIN values of the low-expression group (27.9 ؎ 12.6%, n ‫؍‬ 18) were significantly (p < 0.01) higher than those of normal breast tissues (9.2 ؎ 2.6%, n ‫؍‬ 6), and those of the high-expression group (38.0 ؎ 12.7%, n ‫؍‬ 14) were significantly (p < 0.05) higher than those of the low-expression group. STK15/BTAK mRNA expression showed a significant (p < 0.05) correlation with high histological grade and negativity of estrogen and progesterone receptors. Our results demonstrate that STK15/BTAK mRNA is over-expressed in the majority of breast cancers and its over-expression is significantly associated with CIN, implicating STK15/BTAK in carcinogenesis through induction of CIN. STK15/BTAK mRNA levels might be useful as an indicator of poor prognosis and resistance to endocrine therapy. © 2001 Wiley-Liss, Inc. Key words: STK15/BTAK; real-time RT-PCR; chromosomal instability; centrosome; breast cancerA centrosomal serine/threonine kinase, serine/threonine kinase 15/breast tumor amplified kinase (STK15/BTAK, approved gene symbols are aurora2, ARK1, AIK1), has been identified as an oncogene. [1][2][3][4] It has been shown by in vitro study using NIH-3T3 cells that over-expression of STK15/BTAK induces amplification of centrosomes. 4 Since the centrosomes play an essential role in chromosomal segregation during cell division through establishment of bipolar spindles, their amplification leads to chromosomal instability (CIN). These changes induced by STK15/BTAK overexpression are speculated to result in the transformation of cells. 4 Amplification of the STK15/BTAK gene as well as over-expression of STK15/BTAK mRNA and protein have been reported in human breast cancers, 1,4,5 indicating that STK15/BTAK may be involved in the pathogenesis of human breast cancer. In these reports, however, the most important issue, i.e., association of STK15/BTAK overexpression with CIN, has never been studied. If STK15/BTAK overexpression plays a significant role in pathogenesis, breast cancers with STK15/BTAK over-expression are supposed to show CIN. In the present study, we quantified STK15/BTAK mRNA levels using realtime PCR and compared them with CIN values determined by FISH analysis of chromosomes 1, 11 and 17 in human breast cancers. Correlations of STK15...

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Section: Abstract: Stk15/btak; Real-time Rt-pcr; Chromosomal Instabimentioning

confidence: 99%

Association of centrosomal kinaseSTK15/BTAK mRNA expression with chromosomal instability in human breast cancers

et al. 2001

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“…All of these homologs associate with mitotic structures such as the spindle and the centrosome, and both the message and protein levels are cell-cycle regulated. Among the Aurora/IPL1 kinase family, human AIK/STK15/BTAK/ARK1/AuroraII (Bischo et al, 1998;Kimura et al, 1997;Shindo et al, 1998;Zhou et al, 1998) and mouse IAK1/AYK1 (Gopalan et al, 1997;Yanai et al, 1997) appear to constitute a subfamily, because these protein kinases have closely related N-terminal as well as C-terminal kinase domains. Here we refer to these proteins as Aurora2 according to a recent review (Bischo and Plowman, 1999).…”

Section: Introductionmentioning

confidence: 99%

Degradation of human Aurora2 protein kinase by the anaphase-promoting complex-ubiquitin-proteasome pathway

et al. 2000

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Human Aurora2 was originally identi®ed by its close homology to yeast IPL1 and¯y aurora, which are key regulators of chromosome segregation and a family of serine/threonine kinases. Here we demonstrate that the Aurora2 protein is degraded rapidly after G2/M phase release in mammalian cells. Aurora2 protein has a rapid turnover rate with a half-life of approximately 2 h. In eukaryotic cells, the ubiquitin-proteasome pathway is the major mechanism for the targeted degradation of unstable proteins. The treatment of mammalian cells with proteasome inhibitors blocks Aurora2 degradation. Furthermore, Aurora2 is polyubiquitinated in vivo and in vitro using anaphase-promoting complex (APC). These results demonstrate that Aurora2 protein is turned over through the APC-ubiquitin-proteasome pathway.

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“…The Aurora2/BTAK/STK15 gene is localized on chromosome 20q13, the area amplified in a variety of human cancers. Recently, several groups have reported the overexpression of Aurora2/BTAK/STK15 in 12% of primary breast cancers, more than 50% of primary colorectal cancers, and other solid tumour cell lines (Kimura et al, 1997;Sen et al, 1997;Bischoff et al, 1998). Also, overexpression of this kinase in NIH3T3 cells results in aberration in chromosomes and transformation of the cells (Zhou et al, 1998).…”

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confidence: 99%

Aurora2/BTAK/STK15 is involved in cell cycle checkpoint and cell survival of aggressive non‐Hodgkin's lymphoma

et al. 2003

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Summary. Non‐Hodgkin's lymphoma (NHL) has a wide biological heterogeneity and shows extremely variable responses to therapeutic measures. However, markers that indicate disease activity and determine treatment strategies for this malignancy are little recognized. Using the differential display method, we have identified Aurora2/BTAK/STK15, a centrosome‐associated serine/threonine kinase, whose overexpression leads to centrosome amplification, chromosomal instability and transformation of mammalian solid tumours. Northern analysis with mRNA from a single tumour cell suspension of NHL confirmed that Aurora2/BTAK/STK15 was highly expressed in histologically aggressive types. To elucidate the function of Aurora2/BTAK/STK15 in NHL, Aurora2/BTAK/STK15 sense or antisense genes were transfected to B‐cell lymphoma cell lines to generate overexpressed or under‐regulated tumour cells. Aurora2/BTAK/STK15 antisense transfectant was barely established compared with a sense or vector‐only transfectant. Two clones were finally established that exhibited a low proliferation rate and significantly increased G1 arrest compared with vector‐only transfectants. Moreover, antisense oligo treatment in vitro showed that restriction of cell growth appeared in proportion to antisense oligo concentration. These results suggest that Aurora2/BTAK/STK15 is an effective candidate to indicate not only disease activity but also tumorigenesis of non‐Hodgkin's lymphoma. Retardation of tumour cell growth resulting from the restriction of this gene's functions may be a novel therapeutic approach for non‐Hodgkin's lymphoma.

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Cell Cycle-dependent Expression and Spindle Pole Localization of a Novel Human Protein Kinase, Aik, Related to Aurora of Drosophila and Yeast Ipl1

Cited by 239 publications

References 33 publications

Association of centrosomal kinaseSTK15/BTAK mRNA expression with chromosomal instability in human breast cancers

Association of centrosomal kinaseSTK15/BTAK mRNA expression with chromosomal instability in human breast cancers

Degradation of human Aurora2 protein kinase by the anaphase-promoting complex-ubiquitin-proteasome pathway

Aurora2/BTAK/STK15 is involved in cell cycle checkpoint and cell survival of aggressive non‐Hodgkin's lymphoma

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