David Partida

Spanish National Cancer Research Centre

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Marcos Malumbres

Institut Català de Ciències del Clima

Marianna Trakala

Massachusetts Institute of Technology

María Salazar‐Roa

Universidad Complutense de Madrid

MÁ

Mónica Álvarez‐Fernández

Spanish National Cancer Research Centre

María Maroto

Institute for Animal Reproduction

Andrea Galmozzi

University of Wisconsin–Madison

Enrique Sáez

Scripps Research Institute

Belén Sanz‐Castillo

Pfizer (Spain)

Guillermo de Cárcer

Universidad Autónoma de Madrid

Gonzalo Fernández‐Miranda

Institute for Research in Biomedicine

Cooperative Institutions

Spanish National Cancer Research Centre

Centro de Investigación del Cáncer

Scripps Research Institute

Consejo Superior de Investigaciones Científicas

Instituto de Salud Carlos III

Universidad Autónoma de Madrid

Centro Nacional de Epidemiología

Centre for Biomedical Network Research on Rare Diseases

Scripps Institution of Oceanography

Scripps (United States)

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Activation of the endomitotic spindle assembly checkpoint and thrombocytopenia in Plk1-deficient mice

Blood (2015)

Marianna Trakala David Partida María Salazar‐Roa María Maroto Paulina Wachowicz

PLK1

Multipolar spindles

Polo-like kinase

Spindle checkpoint

Mitotic catastrophe

Spindle pole body

10.1182/blood-2015-03-634402

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Citations (20)

Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes

Nature Chemical Biology (2013)

Eduardo Domínguez Andrea Galmozzi Jae Won Chang Ku‐Lung Hsu Joanna Pawlak

Phenotypic screening

Serine hydrolase

Carboxylesterase

10.1038/nchembio.1429

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Citations (119)

Therapeutic relevance of the PP2A-B55 inhibitory kinase MASTL/Greatwall in breast cancer

Cell Death and Differentiation (2017)

Mónica Álvarez‐Fernández María Sanz‐Flores Belén Sanz‐Castillo María Salazar‐Roa David Partida

PP2A is a major tumor suppressor whose inactivation is frequently found in a wide spectrum of human tumors. In particular, deletion or epigenetic silencing of genes encoding the B55 family of PP2A regulatory subunits is a common feature of breast cancer cells. A key player in the regulation of PP2A/B55 phosphatase complexes is the cell cycle kinase MASTL (also known as Greatwall). During cell division, inhibition of PP2A-B55 by MASTL is required to maintain the mitotic state, whereas inactivation of MASTL and PP2A reactivation is required for mitotic exit. Despite its critical role in cell cycle progression in multiple organisms, its relevance as a therapeutic target in human cancer and its dependence of PP2A activity is mostly unknown. Here we show that MASTL overexpression predicts poor survival and shows prognostic value in breast cancer patients. MASTL knockdown or knockout using RNA interference or CRISPR/Cas9 systems impairs proliferation of a subset of breast cancer cells. The proliferative function of MASTL in these tumor cells requires its kinase activity and the presence of PP2A-B55 complexes. By using a new inducible CRISPR/Cas9 system in breast cancer cells, we show that genetic ablation of MASTL displays a significant therapeutic effect in vivo. All together, these data suggest that the PP2A inhibitory kinase MASTL may have both prognostic and therapeutic value in human breast cancer.

10.1038/s41418-017-0024-0

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Citations (80)

Aurora B Overexpression Causes Aneuploidy and p21^Cip1 Repression during Tumor Development

Molecular and Cellular Biology (2015)

Alejandra González‐Loyola Gonzalo Fernández‐Miranda Marianna Trakala David Partida Kumiko Samejima

Aurora kinase B, one of the three members of the mammalian Aurora kinase family, is the catalytic component of the chromosomal passenger complex, an essential regulator of chromosome segregation in mitosis. Aurora B is overexpressed in human tumors although whether this kinase may function as an oncogene in vivo is not established. Here, we report a new mouse model in which expression of the endogenous Aurkb locus can be induced in vitro and in vivo. Overexpression of Aurora B in cultured cells induces defective chromosome segregation and aneuploidy. Long-term overexpression of Aurora B in vivo results in aneuploidy and the development of multiple spontaneous tumors in adult mice, including a high incidence of lymphomas. Overexpression of Aurora B also results in a reduced DNA damage response and decreased levels of the p53 target p21(Cip1) in vitro and in vivo, in line with an inverse correlation between Aurora B and p21(Cip1) expression in human leukemias. Thus, overexpression of Aurora B may contribute to tumor formation not only by inducing chromosomal instability but also by suppressing the function of the cell cycle inhibitor p21(Cip1).

10.1128/mcb.01286-14

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Citations (99)

Cdk4 and Cdk6 cooperate in counteracting the INK4 family of inhibitors during murine leukemogenesis

Blood (2014)

Esther Rodríguez Víctor Quereda Florian Bellutti Michaela Prchal‐Murphy David Partida

Cyclin-dependent kinase 6

10.1182/blood-2014-02-555292

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Citations (28)

Thrombocytopenia-associated mutations in Ser/Thr kinase MASTL deregulate actin cytoskeletal dynamics in platelets

Journal of Clinical Investigation (2018)

Begoña Hurtado Marianna Trakala Pilar Ximénez‐Embún Aicha El Bakkali David Partida

MASTL, a Ser/Thr kinase that inhibits PP2A-B55 complexes during mitosis, is mutated in autosomal dominant thrombocytopenia. However, the connections between the cell-cycle machinery and this human disease remain unexplored. We report here that, whereas Mastl ablation in megakaryocytes prevented proper maturation of these cells, mice carrying the thrombocytopenia-associated mutation developed thrombocytopenia as a consequence of aberrant activation and survival of platelets. Activation of mutant platelets was characterized by hyperstabilized pseudopods mimicking the effect of PP2A inhibition and actin polymerization defects. These aberrations were accompanied by abnormal hyperphosphorylation of multiple components of the actin cytoskeleton and were rescued both in vitro and in vivo by inhibiting upstream kinases such as PKA, PKC, or AMPK. These data reveal an unexpected role of Mastl in actin cytoskeletal dynamics in postmitotic cells and suggest that the thrombocytopenia-associated mutation in MASTL is a pathogenic dominant mutation that mimics decreased PP2A activity resulting in altered phosphorylation of cytoskeletal regulatory pathways.

Hyperphosphorylation

10.1172/jci121876

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Citations (25)

Identification of Regulatory Elements That Control PPARγ Expression in Adipocyte Progenitors

PLoS ONE (2013)

Wen-Ling Chou Andrea Galmozzi David Partida Kevin Kwan H.C.L. Au Yeung

Adipose tissue renewal and obesity-driven expansion of fat cell number are dependent on proliferation and differentiation of adipose progenitors that reside in the vasculature that develops in coordination with adipose depots. The transcriptional events that regulate commitment of progenitors to the adipose lineage are poorly understood. Because expression of the nuclear receptor PPARγ defines the adipose lineage, isolation of elements that control PPARγ expression in adipose precursors may lead to discovery of transcriptional regulators of early adipocyte determination. Here, we describe the identification and validation in transgenic mice of 5 highly conserved non-coding sequences from the PPARγ locus that can drive expression of a reporter gene in a manner that recapitulates the tissue-specific pattern of PPARγ expression. Surprisingly, these 5 elements appear to control PPARγ expression in adipocyte precursors that are associated with the vasculature of adipose depots, but not in mature adipocytes. Characterization of these five PPARγ regulatory sequences may enable isolation of the transcription factors that bind these cis elements and provide insight into the molecular regulation of adipose tissue expansion in normal and pathological states.

PRDM16

10.1371/journal.pone.0072511

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Citations (6)

AMPK and PFKFB3 mediate glycolysis and survival in response to mitophagy during mitotic arrest

Nature Cell Biology (2015)

Elena B. Domènech Carolina Maestre Lorena Esteban‐Martínez David Partida Rosa Pascual

Mitotic catastrophe

Mitotic exit

10.1038/ncb3231

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Citations (245)