Greatwall Kinase Participates in the Cdc2 Autoregulatory Loop in Xenopus Egg Extracts

Yu, Jiangtao; Zhao, Yong; Li, ZeXiao; Galas, Simon; Goldberg, Michael L.

doi:10.1016/j.molcel.2006.02.022

Cited by 154 publications

(264 citation statements)

References 35 publications

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“…From the limited number of studies on MASTL up to date, it has become clear that this protein plays an important role in the G 2 -M phase of the cell cycle (29,30), and our data confirm that. Depletion of Greatwall kinase, the Xenopus homolog of MASTL, prevented mitotic entry in Xenopus egg extracts (29,30). This finding was later confirmed in human cells, where nearly complete knockdown of MASTL led to a severe delay in mitotic entry (31,32).…”

Section: Discussionsupporting

confidence: 80%

Genome-wide siRNA Screen Identifies the Radiosensitizing Effect of Downregulation of MASTL and FOXM1 in NSCLC

Nagel

Walsum

Buijze

et al. 2015

Molecular Cancer Therapeutics

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Lung cancer is the most common cancer worldwide and on top of that has a very poor prognosis, which is reflected by a 5-year survival rate of 5% to 15%. Radiotherapy is an integral part of most treatment regimens for this type of tumor, often combined with radiosensitizing cytotoxic drugs. In this study, we identified many genes that could potentially be exploited for targeted radiosensitization using a genome-wide siRNA screen in non-small cell lung cancer (NSCLC) cells. The screen identified 433 siRNAs that potentially sensitize lung cancer cells to radiation. Validation experiments showed that knockdown of expression of Forkhead box M1 (FOXM1) or microtubuleassociated serine/threonine kinase-like (MASTL) indeed causes radiosensitization in a panel of NSCLC cells. Strikingly, this effect was not observed in primary human fibroblasts, suggesting that the observed radiosensitization is specific for cancer cells. Phosphoproteomics analyses with and without irradiation showed that a number of cell-cycle-related proteins were significantly less phosphorylated after MASTL knockdown in comparison to the control, while there were no changes in the levels of phosphorylation of DNA damage response proteins. Subsequent analyses showed that MASTL knockdown cells respond differently to radiation, with a significantly shortened G 2 -M phase arrest and defects in cytokinesis, which are followed by a cell-cycle arrest. In summary, we have identified many potential therapeutic targets that could be used for radiosensitization of NSCLC cells, with MASTL being a very promising and druggable target to combine with radiotherapy.

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Section: Discussionsupporting

confidence: 80%

Genome-wide siRNA Screen Identifies the Radiosensitizing Effect of Downregulation of MASTL and FOXM1 in NSCLC

Nagel

Walsum

Buijze

et al. 2015

Molecular Cancer Therapeutics

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“…Greatwall is a unique kinase whose role is essential in Xenopus egg extracts to promote mitotic entry and to maintain the mitotic state (8,10,11). Here, we identified MAST-L as the functional human ortholog of Gwl and demonstrated that its role is evolutionary conserved from Xenopus to human cells.…”

Section: Discussionmentioning

confidence: 86%

“…It has been previously shown that depletion of Gwl in Xenopus egg extracts both prevents mitotic entry and promotes mitotic exit (8,10,11).…”

Section: Mast-l Is the Functional Human Homolog Of Xenopus Greatwallmentioning

confidence: 99%

“…It is a member of the AGC family of serine/threonine kinases that phosphorylates substrates on S/T residues encircled by basic amino acids (7). Work done in Xenopus egg extracts suggested that Gwl promoted mitotic entry by controlling the auto-amplification loop of cyclin B/Cdc2 (8,9). However, it has been recently demonstrated that the main role of this kinase is not the regulation of cyclin B-Cdc2 activity but the inhibition of PP2A, the phosphatase that de-phosphorylates cyclin B-Cdc2 substrates (10,11).…”

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confidence: 99%

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Loss of human Greatwall results in G2 arrest and multiple mitotic defects due to deregulation of the cyclin B-Cdc2/PP2A balance

Burgess

Vigneron

Brioudes

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

640

605

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Here we show that the functional human ortholog of Greatwall protein kinase (Gwl) is the microtubule-associated serine/threonine kinase-like protein, MAST-L. This kinase promotes mitotic entry and maintenance in human cells by inhibiting protein phosphatase 2A (PP2A), a phosphatase that dephosphorylates cyclin B-Cdc2 substrates. The complete depletion of Gwl by siRNA arrests human cells in G2. When the levels of this kinase are only partially depleted, however, cells enter into mitosis with multiple defects and fail to inactivate the spindle assembly checkpoint (SAC). The ability of cells to remain arrested in mitosis by the SAC appears to be directly proportional to the amount of Gwl remaining. Thus, when Gwl is only slightly reduced, cells arrest at prometaphase. More complete depletion correlates with the premature dephosphorylation of cyclin B-Cdc2 substrates, inactivation of the SAC, and subsequent exit from mitosis with severe cytokinesis defects. These phenotypes appear to be mediated by PP2A, as they could be rescued by either a double Gwl/PP2A knockdown or by the inhibition of this phosphatase with okadaic acid. These results suggest that the balance between cyclin B-Cdc2 and PP2A must be tightly regulated for correct mitotic entry and exit and that Gwl is crucial for mediating this regulation in somatic human cells.spindle assembly checkpoint | cell cycle | phosphatase | kinase | slippage I n eukaryotic cells, the mitotic state is maintained by the mitotic kinase cyclin B-Cdc2. Historically, mitotic entry and exit was thought to be the direct consequence of cyclin B-Cdc2 activation and inactivation, respectively (1). Recent results have expanded this model to include phosphatases (2). Specifically, recent evidence indicates that protein phosphatase 2A (PP2A) is responsible for dephosphorylation of cyclin B-Cdc2 substrates and that the regulation of this dephosphorylation is required in mitotic entry and exit (3). This finding suggests a previously unexplored model in which the balance between cyclin B-Cdc2 and PP2A controls mitotic entry and exit. Thus, during G2 PP2A activity is high and cyclin B-Cdc2 activity low, thereby preventing phosphorylation of mitotic substrates, whereas at mitotic entry the balance flips, allowing entry into mitosis. The mechanisms controlling cyclin B-Cdc2 activity have been largely described (4). Briefly, cyclin B-Cdc2 is inhibited during G2 by inhibitory phosphorylations on threonine 14 and tyrosine 15 by Wee1 and Myt1 kinases. Upon mitotic entry, these are removed by the Cdc25 phosphatase (4). Finally, at mitotic exit cyclin B-Cdc2 is inhibited by the ubiquitin-dependent degradation of its regulatory subunit cyclin B (5). Unlike cyclin B-Cdc2 regulation, very little is known about the mechanisms controlling PP2A activity during mitosis, and therefore our understanding of G2 and mitosis is incomplete.Recently, Greatwall (Gwl), a unique critical mitotic regulator, has been discovered in Drosophila (6, 7). It is a member of the AGC family of serine/threonine kinases that ph...

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“…Le gène Gwl est conservé de la drosophile jusqu'à l'homme. Les premières études réalisées chez le xénope montrent que l'élimination de la protéine kinase Gwl induit une inhibition de l'entrée en phase M ou bien une sortie prématurée de mitose [3]. Ces travaux suggèrent que Gwl est requise pour maintenir l'état mitotique en jouant un rôle dans la boucle d'amplification du MPF.…”

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Greatwall, un nouveau gardien de la mitose

et al. 2011

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Greatwall Kinase Participates in the Cdc2 Autoregulatory Loop in Xenopus Egg Extracts

Cited by 154 publications

References 35 publications

Genome-wide siRNA Screen Identifies the Radiosensitizing Effect of Downregulation of MASTL and FOXM1 in NSCLC

Genome-wide siRNA Screen Identifies the Radiosensitizing Effect of Downregulation of MASTL and FOXM1 in NSCLC

Loss of human Greatwall results in G2 arrest and multiple mitotic defects due to deregulation of the cyclin B-Cdc2/PP2A balance

Greatwall, un nouveau gardien de la mitose

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