Targeted disruption of Aurora A causes abnormal mitotic spindle assembly, chromosome misalignment and embryonic lethality

Sasai, Kaori; Parant, John M.; Brandt, Mark; Carter, Jennifer L.; Adams, H. R.; Stass, Sanford A.; Killary, Ann M.; Katayama, Hiroshi; Sen, Subrata

doi:10.1038/onc.2008.47

Cited by 69 publications

(68 citation statements)

References 32 publications

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“…In addition, the mouse genome contains several aurora C loci originally considered to be pseudogenes but that might express functional proteins (Yang et al, 2010) thus making difficult to evaluate a loss-of-function aurora C mutant in this organism. Lack of aurora A results in lethality at the morula/blastocyst stage due to defective formation of a mitotic bipolar spindle, thus confirming the functional differences between aurora A and aurora B/C in vivo (Ang et al, 2008;Cowley et al, 2009;Sasai et al, 2008). Together, these results suggest that aurora C is the major CPC kinase during these early cell divisions in vivo.…”

Section: Discussionsupporting

confidence: 68%

Genetic disruption of aurora B uncovers an essential role for aurora C during early mammalian development

Fernández-Miranda

Trakala

Martı́n³

et al. 2011

Development

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SUMMARYMitosis is controlled by multiple kinases that drive cell cycle progression and prevent chromosome mis-segregation. Aurora kinase B interacts with survivin, borealin and incenp to form the chromosomal passenger complex (CPC), which is involved in the regulation of microtubule-kinetochore attachments and cytokinesis. Whereas genetic ablation of survivin, borealin or incenp results in early lethality at the morula stage, we show here that aurora B is dispensable for CPC function during early cell divisions and aurora B-null embryos are normally implanted. This is due to a crucial function of aurora C during these early embryonic cycles. Expression of aurora C decreases during late blastocyst stages resulting in post-implantation defects in aurora B-null embryos. These defects correlate with abundant prometaphase figures and apoptotic cell death of the aurora B-deficient inner cell mass. Conditional deletion of aurora B in somatic cells that do not express aurora C results in chromosomal misalignment and lack of chromosome segregation. Re-expression of wild-type, but not kinase-dead, aurora C rescues this defect, suggesting functional overlap between these two kinases. Finally, aurora B-null cells partially arrest in the presence of nocodazole, suggesting that this kinase is not essential for the spindle assembly checkpoint.

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Section: Discussionsupporting

confidence: 68%

Genetic disruption of aurora B uncovers an essential role for aurora C during early mammalian development

Fernández-Miranda

Trakala

Martı́n³

et al. 2011

Development

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“…All these features are also found in Aurora A null primary MEFs (15,31,32), which is consistent with the role of Tpx2 as a critical regulator of the Aurora A kinase (4,6,8,(33)(34)(35). However, some differences are detected between these 2 models suggesting separate functions.…”

Section: Discussionsupporting

confidence: 62%

“…For instance, conditional genetic ablation of Tpx2, but not Aurora A, results in a significant induction of apoptosis in primary MEFs. In addition, whereas monopolar spindles are rare in Tpx2 null cells, these figures are frequently observed in Aurora A-deficient fibroblasts MEFs (15,31,32), suggesting that this kinase plays a major role in centrosome maturation and separation in a Tpx2-independent manner.…”

Section: Discussionmentioning

confidence: 99%

“…Genetic ablation of Eg-5 (kinesin-5), a plus-enddirected motor involved in bipolar spindle formation and maintenance during mitosis, is also associated with early embryonic lethality mainly due to the accumulation of monopolar cells arrested in prometaphase that collapse and are not able to progress beyond the blastocyst stage (29,30). Interestingly, embryos deficient for Aurora A, probably the main mitotic kinase involved in spindle formation, are also arrested at the same early stages of development (15,31,32). Thus, the lack of proteins with major functions in spindle formation and maintenance seems to prevent embryonic development at very early stages.…”

Section: Discussionmentioning

confidence: 99%

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Tpx2 Controls Spindle Integrity, Genome Stability, and Tumor Development

et al. 2012

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Tpx2 is a microtubule-associated protein that activates the cell-cycle kinase Aurora A and regulates the mitotic spindle. Overexpression of Tpx2 is associated with the development of different human tumors and strongly correlates with chromosomal instability. By analyzing a conditional null mutation in the mouse Tpx2 gene, we show here that Tpx2 expression is essential for spindle function and chromosome segregation in the mouse embryo. Conditional genetic ablation of Tpx2 in primary cultures resulted in deficient microtubule nucleation from DNA and aberrant spindles during prometaphase. These cells eventually exited from mitosis without chromosome segregation. In addition, Tpx2 haploinsufficiency led to the accumulation of aneuploidies in vivo and increased susceptibility to spontaneous lymphomas and lung tumors. Together, our findings indicate that Tpx2 is essential for maintaining genomic stability through its role in spindle regulation. Subtle changes in Tpx2 expression may favor tumor development in vivo. Cancer Res; 72(6); 1518-28. Ó2012 AACR.

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“…AAK controls centrosome maturation (7)(8)(9), mitotic spindle assembly (2,5), and other mitotic progression events by phosphorylating various substrates (2). AAK perturbation results in mitotic spindle defects, mitotic delay, and cell death (10)(11)(12)(13)(14)(15). Several lines of evidence support a link between increased AAK expression and tumorigenesis: AAK overexpression is associated with the aneuploidy and centrosome amplification commonly seen in tumor cells (16); AAK overexpression has been reported in a variety of solid tumors and hematologic malignancies (16)(17)(18)(19)(20)(21)(22)(23); furthermore, AAK is oncogenic and can transform normal cells in experimental systems (16,23).…”

Section: Introductionmentioning

confidence: 99%

Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors

Cervantes

Élez

Roda

et al. 2012

Clinical Cancer Research

131

159

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Purpose: Aurora A kinase (AAK) is a key regulator of mitosis and a target for anticancer drug development. This phase I study investigated the safety, pharmacokinetics, and pharmacodynamics of MLN8237 (alisertib), an investigational, oral, selective AAK inhibitor, in 59 adults with advanced solid tumors.Experimental Design: Patients received MLN8237 once daily or twice daily for 7, 14, or 21 consecutive days, followed by 14 days recovery, in 21-, 28-, or 35-day cycles. Dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) for the 7-and 21-day schedules were determined. Pharmacokinetic parameters were derived from plasma concentration-time profiles. AAK inhibition in skin and tumor biopsies was evaluated and antitumor activity assessed.Results: Neutropenia and stomatitis were the most common DLTs. The MTD for the 7-and 21-day schedules was 50 mg twice daily and 50 mg once daily, respectively. MLN8237 absorption was fast (median time to maximum concentration, 2 hours). Mean terminal half-life was approximately 19 hours. At steady state, pharmacodynamic effects were shown by accumulation of mitotic and apoptotic cells in skin, and exposure-related increases in numbers of mitotic cells with characteristic spindle and chromosomal abnormalities in tumor specimens, supporting AAK inhibition by MLN8237. Stable disease was observed and was durable with repeat treatment cycles, administered over 6 months, in 6 patients, without notable cumulative toxicity.Conclusions: The recommended phase II dose of MLN8237 is 50 mg twice daily on the 7-day schedule, which is being evaluated further in a variety of malignancies, including in a phase III trial in peripheral T-cell lymphoma.

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Targeted disruption of Aurora A causes abnormal mitotic spindle assembly, chromosome misalignment and embryonic lethality

Cited by 69 publications

References 32 publications

Genetic disruption of aurora B uncovers an essential role for aurora C during early mammalian development

Genetic disruption of aurora B uncovers an essential role for aurora C during early mammalian development

Tpx2 Controls Spindle Integrity, Genome Stability, and Tumor Development

Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors

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