Role of Survivin Phosphorylation by Aurora B in Mitosis

Delacour-Larose, Marlène; Thi, My Nhung Hoang; Dimitrov, Stéfan; Molla, Annie

doi:10.4161/cc.6.15.4482

Cited by 44 publications

(48 citation statements)

References 19 publications

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“…That both survivin and Aurora B inactivation leads to the same phenotype is quite expected because function of both proteins is interdependent with Aurora B regulating survivin localization by phosphorylation, and survivin is being required for appropriate Aurora B localization. [42][43] However, our data show that, whereas Aurora B inactivation is dispensable for MK polyploidization, it is absolutely required for accomplishment of a complete endomitotic process. Indeed, in most Aurora B inhibitor-treated endomitotic MKs, mitotic failure occurs at the metaphase/anaphase transition because of incomplete chromosome segregation and not because of a failure in late cytokinesis.…”

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confidence: 39%

Aurora B is dispensable for megakaryocyte polyploidization, but contributes to the endomitotic process

Lordier

Chang

Jalil

et al. 2010

Blood

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Polyploidization of megakaryocytes (MKs), the platelet precursors, occurs by endomitosis, a mitotic process that fails at late stages of cytokinesis. Expression and function of Aurora B kinase during endomitosis remain controversial. Here, we report that Aurora B is normally expressed during the human MK endomitotic process. Aurora B localized normally in the midzone or midbody during anaphase and telophase in low ploidy megakaryocytes and in up to 16N rare endomitotic MKs was observed. Aurora B was also functional during cytokinesis as attested by phosphorylation of both its activation site and MgcRacGAP, its main substrate. However, despite its activation, Aurora B did not prevent furrow regression. Inhibition of Aurora B by AZD1152-HQPA decreased cell cycle entry both in 2N to 4N and polyploid MKs and induced apoptosis mainly in 2N to 4N cells. In both MK classes, AZD1152-HQPA induced p53 activation and retinoblastoma hypophosphorylation. Resistance of polyploid MKs to apoptosis correlated to a high BclxL level. Aurora B inhibition did not impair MK polyploidization but profoundly modified the endomitotic process by inducing a mis-segregation of chromosomes and a mitotic failure in anaphase. This indicates that Aurora B is dispensable for MK polyploidization but is necessary to achieve a normal endomitotic process. (Blood. 2010;116(13):2345-2355) IntroductionMegakaryocytes (MKs) are the hematopoietic cells that produce platelets. During differentiation, MKs undergo a unique mode of cell cycle called endomitosis that corresponds to an incomplete multipolar mitosis characterized by failure of both nuclear (karyokinesis) and cytoplasmic division (cytokinesis). It was considered that MK endomitosis was similar to a mitotic failure in anaphase without cleavage furrow formation. 1,2 However, 3 recent reports have shown that the switch from mitosis to endomitosis corresponds to a late failure of cytokinesis, [3][4][5] probably because of an abnormal contractile ring. 4 The structure of the central spindle in MKs, another major regulator of cytokinesis, has also been a matter of debate. 4,[6][7][8][9][10] However, recent reports in human MKs underscored its normal organization. 4,6 Aurora B kinase is a member of a growing family of chromosomal passenger proteins that change their subcellular localization during mitosis. Aurora B is associated with chromosomes during prophase, with inner centromeres during metaphase and early anaphase, and with the midzone and midbody during late anaphase and telophase. 11-13 Aurora B activity depends on its association with other chromosome passenger proteins (INCENP, Borealin, and survivin) as well as its autophosphorylation at threonine 232 (Thr232) located in the activating loop. 14 Aurora B is essential for mitosis and cytokinesis. 15,16 Aurora B is involved in chromosome congression at metaphase and chromosome separation at anaphase. One of the main Aurora B kinase substrate is MgcRacGAP. Phosphorylation of the GAP domain at serine 387 (Ser387) by Aurora B converts MgcRacGAP to ...

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confidence: 39%

Aurora B is dispensable for megakaryocyte polyploidization, but contributes to the endomitotic process

Lordier

Chang

Jalil

et al. 2010

Blood

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“…It will be interesting to investigate how this interaction cross-talks with the "sensor" function of CPC in monitoring the kinetochore-microtubule attachment. 48 Additionally, functional interplay between the Aurora-A regulated and Shugosin 1 and 2 (Sgo1 and Sgo2) mediated pathways implicated in kinetochore driven formation of microtubules 49 and localization as well as regulation of the CPC checkpoint functions 50 remain relevant subjects worthy of detailed analyses for proper elucidation of the mechanisms underlying these processes.…”

Section: © 2 0 0 8 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

Aurora kinase-A regulates kinetochore/chromatin associated microtubule assembly in human cells

et al. 2008

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Microtubule nucleation and formation from the kinetochore/ chromatin have been proposed to contribute to bipolar spindle assembly facilitating equal segregation of chromosomes in mitosis. Although two independent pathways involving the small Ran GTPase-TPX2 proteins and the chromosomal passenger complex proteins have been implicated in the formation of microtubules from the kinetochore/chromatin, detailed molecular mechanisms integrating the pathways and regulating the process have not been well elucidated. This study demonstrates that Aurora kinase-A plays a central role in the kinetochore/chromatin associated microtubule assembly in human cells by integrating the two pathways regulating the process. Silencing by siRNA and overexpression of a kinase inactive mutant revealed involvement of Aurora-A at two critical steps. These include formation of γ-tubulin foci in the vicinity of kinetochore/chromatin to create microtubule nucleation sites as well as INCENP and TPX2 mediated activation of Aurora-A facilitating formation and stabilization of microtubules. The findings provide the first evidence of Aurora-A, in association with INCENP and TPX2, being a key regulator of kinetochore/ chromatin associated microtubule formation in human cells.

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“…In early mitosis, the CPC promotes correct chromosome alignment and is responsible for the displacement of HP-1 from mitotic chromosomes by modifying histone H3, whereas at the end of mitosis, CPC regulates proper completion of cytokinesis (23,24). The non-enzymatic components of this complex control the targeting, enzymatic activity, and stability of Aurora B kinase (25)(26)(27)(28), and although the major role of CPC is in mitosis, its components are already expressed earlier in the cell cycle, when different complexes of chromosomal passenger proteins may exist (29). Recently, for example, Aurora B, INCENP, and Borealin, but not survivin, have been reported to be components of the nucleolar proteome (30).…”

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confidence: 99%

Identification of Myb-binding Protein 1A (MYBBP1A) as a Novel Substrate for Aurora B Kinase

Perrera

Colombo

Valsasina

et al. 2010

Journal of Biological Chemistry

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Aurora kinases are mitotic enzymes involved in centrosome maturation and separation, spindle assembly and stability, and chromosome condensation, segregation, and cytokinesis and represent well known targets for cancer therapy because their deregulation has been linked to tumorigenesis. The availability of suitable markers is of crucial importance to investigate the functions of Auroras and monitor kinase inhibition in in vivo models and in clinical trials. Extending the knowledge on Aurora substrates could help to better understand their biology and could be a source for clinical biomarkers. Using biochemical, mass spectrometric, and cellular approaches, we identified MYBBP1A as a novel Aurora B substrate and serine 1303 as the major phosphorylation site. MYBBP1A is phosphorylated in nocodazole-arrested cells and is dephosphorylated upon Aurora B silencing or by treatment with Danusertib, a small molecule inhibitor of Aurora kinases. Furthermore, we show that MYBBP1A depletion by RNA interference causes mitotic progression delay and spindle assembly defects. MYBBP1A has until now been described as a nucleolar protein, mainly involved in transcriptional regulation. The results presented herein show MYBBP1A as a novel Aurora B kinase substrate and reveal a not yet recognized link of this nucleolar protein to mitosis.

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Role of Survivin Phosphorylation by Aurora B in Mitosis

Cited by 44 publications

References 19 publications

Aurora B is dispensable for megakaryocyte polyploidization, but contributes to the endomitotic process

Aurora B is dispensable for megakaryocyte polyploidization, but contributes to the endomitotic process

Aurora kinase-A regulates kinetochore/chromatin associated microtubule assembly in human cells

Identification of Myb-binding Protein 1A (MYBBP1A) as a Novel Substrate for Aurora B Kinase

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