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Grant support

We thank Diego Megias for help with microscopy and Drs. M. Yoshida, V. Andres, and G. Kops for reagents. M. A-F. and P. P. G. were supported by the European Union-PEOPLE programme and Caja Navarra, respectively. B. S.-C. and M. T. were supported by Foundation La Caixa. R. S.-M. was supported by the Juan de la Cierva programme from the Spanish Ministry of Economy and Competitiveness (MINECO) and Asociacion Espanola contra el Cancer. M.S.-F. was supported by the Formacion de Personal Universitario (FPU) programme and the Spanish Ministry of Education. This work was funded by a grant from Bayer Pharma AG, the Foundation Ramon Areces, MINECO Grant SAF2012-38215, OncoCycle Programme Grant S2010/BMD-2470 from the Comunidad de Madrid, and the European Union Seventh Framework Programme MitoSys (Systems Biology of Mitosis) project Grant HEALTH-F5-2010-241548.

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Sanz-Flores, MariaAuthor

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Article

Greatwall is essential to prevent mitotic collapse after nuclear envelope breakdown in mammals

Publicated to:Proceedings of the National Academy of Sciences of the United States of America. 110 (43): 17374-17379 - 2013-10-22 110(43), DOI: 10.1073/pnas.1310745110

Authors: Alvarez-Fernandez, Monica; Sanchez-Martinez, Ruth; Sanz-Castillo, Belen; Gan, Pei Pei; Sanz-Flores, Maria; Trakala, Marianna; Ruiz-Torres, Miguel; Lorca, Thierry; Castro, Anna; Malumbres, Marcos

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Abstract

Greatwall is a protein kinase involved in the inhibition of protein phosphatase 2 (PP2A)-B55 complexes to maintain the mitotic state. Although its biochemical activity has been deeply characterized in Xenopus, its specific relevance during the progression of mitosis is not fully understood. By using a conditional knockout of the mouse ortholog, Mastl, we show here that mammalian Greatwall is essential for mouse embryonic development and cell cycle progression. Yet, Greatwall-null cells enter into mitosis with normal kinetics. However, these cells display mitotic collapse after nuclear envelope breakdown (NEB) characterized by defective chromosome condensation and prometaphase arrest. Intriguingly, Greatwall is exported from the nucleus to the cytoplasm in a CRM1-dependent manner before NEB. This export occurs after the nuclear import of cyclin B-Cdk1 complexes, requires the kinase activity of Greatwall, and is mediated by Cdk-, but not Polo-like kinase 1-dependent phosphorylation. The mitotic collapse observed in Greatwall-deficient cells is partially rescued after concomitant depletion of B55 regulatory subunits, which are mostly cytoplasmic before NEB. These data suggest that Greatwall is an essential protein in mammals required to prevent mitotic collapse after NEB.

Keywords

Active transport, cell nucleusAmino acid sequenceAnimalsCell cycle regulationCell divisionCell line, tumorCells, culturedChromosomeDrosophilaEmbryo, mammalianEntryFemaleGreatwall protein, mouseHumansKinaseLocalizationLuminescent proteinsMaleMammalsMastMiceMice, knockoutMicroscopy, fluorescenceMicrotubule-associated proteinsMitosisMitotic kinasesMitotic phosphatasesNuclear envelopeNuclear exporNuclear exportProgressionProtein phosphatase 2Protein phosphatase 2aProtein serine-threonine kinasesProtein subunitsRna interferenceSequence homology, amino acidTime factors

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Proceedings of the National Academy of Sciences of the United States of America due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2013, it was in position 4/55, thus managing to position itself as a Q1 (Primer Cuartil), in the category Multidisciplinary Sciences.

From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 8.81, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions May 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-05-30, the following number of citations:

  • WoS: 87
  • Scopus: 92
  • Europe PMC: 71
  • OpenCitations: 99

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-05-30:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 119.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 119 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 46.

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: France.