Bestatin Inhibits Cell Growth, Cell Division, and Spore Cell Differentiation in Dictyostelium discoideum

Poloz, Yekaterina; Catalano, Andrew; O’Day, Danton H.

doi:10.1128/ec.05311-11

Cited by 17 publications

(8 citation statements)

References 52 publications

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“…These results suggest that CBP4a is recruited to the nucleolus by NumA1 in a Ca 2+ -dependent manner as previously suggested by Myre and O’Day [36]. Unlike CBP4a, NumA1-binding partner PsaA colocalizes with NumA1 in the nucleoplasm but not the nucleolus [34,35]. …”

Section: Discussionsupporting

confidence: 80%

“…It was also detected at the nuclear envelope region from prometaphase through telophase. This mitotic redistribution pattern was also similar to that of nuclear PsaA and cdk5, two recently identified cell cycle-linked proteins in Dictyostelium [34,35,42]. It was not possible to determine if FhkA was adjacent to the inner nuclear envelope, outer nuclear envelope, or colocalized with the nuclear envelope, however the pattern was similar to that observed for NumA1.…”

Section: Discussionsupporting

confidence: 72%

“…NumA1 likely interacts with binding-partner puromycin-sensitive aminopeptidase A (PsaA) in the nucleoplasm, since this is where the two colocalize, however its nucleolar binding partner has yet to be identified [34,35]. The only other known NumA1-interacting protein is Ca 2+ -binding protein 4a (CBP4a) suggesting it may also reside in the nucleolus [36].…”

Section: Introductionmentioning

confidence: 99%

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Rad53 homologue forkhead-associated kinase A (FhkA) and Ca2+-binding protein 4a (CBP4a) are nucleolar proteins that differentially redistribute during mitosis in Dictyostelium

Catalano

O’Day

2013

Cell Div

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BackgroundDuring mitosis most nucleolar proteins redistribute to other locales providing an opportunity to study the relationship between nucleolar protein localization and function. Dictyostelium is a model organism for the study of several fundamental biological processes and human diseases but only two nucleolar proteins have been studied during mitosis: NumA1 and Snf12. Both of them are linked to the cell cycle. To acquire a better understanding of nucleolar protein localization and dynamics in Dictyostelium we studied the nucleolar localization of two additional proteins during mitosis: Snf12-linked forkhead-associated kinase A (FhkA), which is involved in the cell cycle, and Ca2+-binding protein 4a (CBP4a), which is a binding partner of NumA1.MethodsPolyclonal antibodies were produced in-house. Cells were fixed and probed with either anti-FhkA or anti-CBP4a in order to determine cellular localization during interphase and throughout the stages of mitosis. Colocalization with DAPI nuclear stain allowed us to determine the location of the nucleus and nucleolus while colocalization with anti-α-tubulin allowed us to determine the cell cycle stage.ResultsHere we verify two novel nucleolar proteins, Rad53 homologue FhkA which localized around the edge of the nucleolus and CBP4a which was detected throughout the entire nucleolus. Treatment with the Ca2+ chelator BAPTA (5 mM) showed that the nucleolar localization of CBP4a is Ca2+-dependent. In response to actinomycin D (0.05 mg/mL) CBP4a disappeared from the nucleolus while FhkA protruded from the nucleus, eventually pinching off as cytoplasmic circles. FhkA and CBP4a redistributed differently during mitosis. FhkA redistributed throughout the entire cell and at the nuclear envelope region from prometaphase through telophase. In contrast, during prometaphase CBP4a relocated to many large, discrete “CBP4a islands” throughout the nucleoplasm. Two larger “CBP4a islands” were also detected specifically at the metaphase plate region.ConclusionsFhkA and CBP4a represent the sixth and seventh nucleolar proteins that have been verified to date in Dictyostelium and the third and fourth studied during mitosis. The protein-specific distributions of all of these nucleolar proteins during interphase and mitosis provide unique insight into nucleolar protein dynamics in this model organism setting the stage for future work.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

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Rad53 homologue forkhead-associated kinase A (FhkA) and Ca2+-binding protein 4a (CBP4a) are nucleolar proteins that differentially redistribute during mitosis in Dictyostelium

Catalano

O’Day

2013

Cell Div

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“…The role of cisplatin on gene expression in the model has been analysed (Van Driessche et al, 2007), in addition to its regulation of mitogen activated protein kinase phosphatases (Moncho-Amor et al, 2011) and in DNA repair pathways (Gunn et al, 2016). The cellular functions of other anti-cancer treatments, such as bestatin and Poly (ADPribose) polymerase inhibitors have also been analysed in D. discoideum (Kolb et al, 2017, Poloz et al, 2012. Finally, Dictyostelium strains have also been shown to provide a source of novel compounds with anti-proliferative properties that could thus be used as cancer treatments (Honma et al, 2018, Kubohara and.…”

Section: Treating Cancer: Lessons From D Discoideummentioning

confidence: 99%

Dictyostelium discoideum as a pharmacological model system to study the mechanisms of medicinal drugs and natural products

Schaf

Damstra-Oddy²,

Williams³

2019

Int. J. Dev. Biol.

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Developing novel compounds for the treatment of diseases remains one of the highest priorities in biomedical research, where it is critical to identify their targets and how they work at a cellular level. Most studies in this area employ mammalian models, since rodents or non-human primates are seen as a good approximation for humans. However, using mammalian models can be problematic for a range of reasons, including high genetic redundancy and the essential role for many proteins in development. More importantly, it is very difficult to identify how compounds function at a cellular or molecular level in these models without a previously suggested mechanism or target. So how can we identify targets of medicinal compounds? In this review we outline the use of an innovative and tractable model system, Dictyostelium discoideum, to provide useful insight to the cellular and molecular functions of both therapeutic drugs and pharmacologically active natural products. We outline the advantages of using this model, and then provide a range of exemplar studies using D. discoideum in pharmacological research to demonstrate breakthroughs in understanding the action and effects of compounds, and the subsequent translational of these advances to mammalian models leading to potential improvements in societal health.KEY WORDS: mechanism of action, natural product, drug discovery, pharmacogenomics, pharmacology Int. J. Dev. Biol. 63: 541-550 (2019)

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“…Yeast two hybrid and co-immunoprecipitation analyses revealed that NumA1 not only binds to nucleolar Cbp4a but also to nuclear PsaA. PsaA shares the critical domains of human Psa including GAMEN and Zinc-binding domains and, similarly, is also inhibited by bestatin methyl ester (BME) [60,85]. DdPsaA has been proven to possess defined NLS and NES sequences.…”

Section: Protein Associates Of Nucleolar Proteinsmentioning

confidence: 99%

Proteins of the Nucleolus of Dictyostelium discoideum: Nucleolar Compartmentalization, Targeting Sequences, Protein Translocations and Binding Partners

O’Day

2019

Cells

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The nucleoli of Dictyostelium discoideum have a comparatively unique, non-canonical, localization adjacent to the inner nuclear membrane. The verified nucleolar proteins of this eukaryotic microbe are detailed while other potential proteins are introduced. Heat shock protein 32 (Hsp32), eukaryotic translation initiation factor 6 (eIF6), and tumour necrosis factor receptor-associated protein 1 (TRAP1) are essential for cell survival. NumA1, a breast cancer type 1 susceptibility protein-C Terminus domain-containing protein linked to cell cycle, functions in the regulation of nuclear number. The cell cycle checkpoint kinase 2 homologue forkhead-associated kinase A (FhkA) and BRG1-associated factor 60a homologue Snf12 are also discussed. While nucleoli appear homogeneous ultrastructurally, evidence for nucleolar subcompartments exists. Nucleolar localization sequences (NoLS) have been defined that target proteins to either the general nucleolar area or to a specific intranucleolar domain. Protein translocations during mitosis are protein-specific and support the multiple functions of the Dictyostelium nucleolus. To enrich the picture, binding partners of NumA1, the most well-characterized nucleolar protein, are examined: nucleolar Ca2+-binding protein 4a (CBP4a), nuclear puromycin-sensitive aminopeptidase A (PsaA) and Snf12. The role of Dictyostelium as a model for understanding the contribution of nucleolar proteins to various diseases and cellular stress is discussed throughout the review.

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Bestatin Inhibits Cell Growth, Cell Division, and Spore Cell Differentiation in Dictyostelium discoideum

Cited by 17 publications

References 52 publications

Rad53 homologue forkhead-associated kinase A (FhkA) and Ca2+-binding protein 4a (CBP4a) are nucleolar proteins that differentially redistribute during mitosis in Dictyostelium

Rad53 homologue forkhead-associated kinase A (FhkA) and Ca2+-binding protein 4a (CBP4a) are nucleolar proteins that differentially redistribute during mitosis in Dictyostelium

Dictyostelium discoideum as a pharmacological model system to study the mechanisms of medicinal drugs and natural products

Proteins of the Nucleolus of Dictyostelium discoideum: Nucleolar Compartmentalization, Targeting Sequences, Protein Translocations and Binding Partners

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