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  • 1.
    Bonczek, Ondrej
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Research Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute (MMCI), Zluty Kopec 7, Brno, Czech Republic.
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gnanasundram, Sivakumar Vadivel
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Chen, Sa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Haronikova, Lucia
    Research Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute (MMCI), Zluty Kopec 7, Brno, Czech Republic.
    Zavadil-Kokas, Filip
    Research Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute (MMCI), Zluty Kopec 7, Brno, Czech Republic.
    Vojtesek, Borivoj
    Research Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute (MMCI), Zluty Kopec 7, Brno, Czech Republic.
    DNA and RNA Binding Proteins: From Motifs to Roles in Cancer2022In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 16, article id 9329Article, review/survey (Refereed)
    Abstract [en]

    DNA and RNA binding proteins (DRBPs) are a broad class of molecules that regulate numerous cellular processes across all living organisms, creating intricate dynamic multilevel networks to control nucleotide metabolism and gene expression. These interactions are highly regulated, and dysregulation contributes to the development of a variety of diseases, including cancer. An increasing number of proteins with DNA and/or RNA binding activities have been identified in recent years, and it is important to understand how their activities are related to the molecular mechanisms of cancer. In addition, many of these proteins have overlapping functions, and it is therefore essential to analyze not only the loss of function of individual factors, but also to group abnormalities into specific types of activities in regard to particular cancer types. In this review, we summarize the classes of DNA-binding, RNA-binding, and DRBPs, drawing particular attention to the similarities and differences between these protein classes. We also perform a cross-search analysis of relevant protein databases, together with our own pipeline, to identify DRBPs involved in cancer. We discuss the most common DRBPs and how they are related to specific cancers, reviewing their biochemical, molecular biological, and cellular properties to highlight their functions and potential as targets for treatment.

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  • 2.
    Chen, Sa
    Umeå University, Faculty of Science and Technology, Molecular Biology (Faculty of Science and Technology).
    Expression and function of Suppressor of zeste 12 in Drosophila melanogaster2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The development of animals and plants needs a higher order of regulation of gene expression to maintain proper cell state. The mechanisms that control what, when and where a gene should (or should not) be expressed are essential for correct organism development. The Polycomb group (PcG) is a family of genes responsible for maintaining gene silencing and Suppressor of zeste 12 (Su(z)12) is one of the core components in the PcG. The gene is highly conserved in organisms ranging from plants to humans, however, the specific function is not well known. The main tasks of this thesis was to investigate the function of Su(z)12 and its expression at different stages of Drosophila development.

    In polytene chromosomes of larval salivary glands, Su(z)12 binds to about 90 specific euchromatic sites. The binding along the chromosome arms is mostly in interbands, which are the most DNA de-condensed regions. The binding sites of Su(z)12 in polytene chromosomes correlate precisely with those of the Enhancer-of-zeste (E(z)) protein, indicating that Su(z)12 mainly exists within the Polycomb Repressive Complex 2 (PRC2). However, the binding pattern does not overlap well with Histone 3 lysine 27 tri-methylations (H3K27me3), the specific chromatin mark created by PRC2. The Su(z)12 binding to chromatin is dynamically regulated during mitotic and meiotic cell division. The two different Su(z)12 isoforms: Su(z)12-A and Su(z)12-B (resulting from alternative RNA splicing), have very different expression patterns during development. Functional analyses indicate that they also have different functions he Su(z)12-B form is the main mediator of silencing. Furthermore, a neuron specific localization pattern in larval brain and a giant larval phenotype in transgenic lines reveal a potential function of Su(z)12-A in neuron development.  In some aspects the isoforms seem to be able to substitute for each other.

    The histone methyltransferase activity of PRC2 is due to the E(z) protein. However, Su(z)12 is also necessary for H3K27me3 methylation in vivo, and it is thus a core component of PRC2. Clonal over-expression of Su(z)12 in imaginal wing discs results in an increased H3K27me3 activity, indicating that Su(z)12 is a limiting factor for silencing. When PcG function is lost, target genes normally become de-repressed. The segment polarity gene engrailed, encoding a transcription factor, is a target for PRC2 silencing. However, we found that it was not activated when PRC2 function was deleted. We show that the Ultrabithorax protein, encoded by another PcG target gene, also acts as an inhibitor of engrailed and that de-regulation of this gene causes a continued repression of engrailed. The conclusion is that a gene can have several negative regulators working in parallel and that secondary effects have to be taken into consideration, when analyzing effects of mutants.

    PcG silencing affects very many cellular processes and a large quantity of knowledge is gathered on the overall mechanisms of PcG regulation. However, little is known about how individual genes are silenced and how cells “remember” their fate through cell generations.

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  • 3.
    Chen, Sa
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Larsson, Anna L.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Tegeling, Erik
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Rasmuson Lestander, Asa
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    In vivo analysis of Suppressor of zeste 12´s different isoformsManuscript (Other academic)
    Abstract [en]

    Polycomb Group (PcG) genes are known to encode a large chromatin-associated family of proteins which are involved in genomic regulation of many cellular processes. Su(z)12 is a key component in PcG silencing. It is needed for three levels of methylation of histone 3 lysine 27 in vivo in Drosophila. Here, we report that Su(z)12 may exist in different isoforms and that these isoforms are spatially and temporally regulated. The biological function of the Su(z)12-A and -B isoforms seems to be very different. For instance the transgenic Su(z)12-B and the human homolog SUZ12, but not Su(z)12-A, rescue Su(z)12 mutants. Furthermore, transgenic flies over-expressing Su(z)12-B show typical homeotic transformation phenotypes, while over-expression of Su(z)12-A does not. However, the two isoforms appears to be able to substitute for each other in some aspects. During larval and pupal stages, Su(z)12-A seems to play the main role. 

  • 4.
    Chen, Sa
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Rasmuson-Lestander, Åsa
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Regulation of the Drosophila engrailed gene by Polycomb repressor complex 22009In: Mechanisms of Development, ISSN 0925-4773, E-ISSN 1872-6356, Vol. 126, no 5-6, p. 443-448Article in journal (Refereed)
    Abstract [en]

    Suppressor-of-zeste-12 (Su(z)12) is a core component of the Polycomb repressive complex 2 (PRC2), which has a methyltransferase activity directed towards lysine residues of histone 3. Mutations in Polycomb group (PcG) genes cause de-repression of homeotic genes and subsequent homeotic transformations. Another target for Polycomb silencing is the engrailed gene, which encodes a key regulator of segmentation in the early Drosophila embryo. In close proximity to the en gene is a Polycomb Response Element, but whether en is regulated by Su(z)12 is not known. In this report, we show that en is not de-repressed in Su(z)12 or Enhancer-of-zeste mutant clones in the anterior compartment of wing discs. Instead, we find that en expression is down-regulated in the posterior portion of wing discs, indicating that the PRC2 complex acts as an activator of en. Our results indicate that this is due to secondary effects, probably caused by ectopic expression of Ubx and Abd-B.

  • 5.
    Chen, Sa
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Rasmuson-Lestander, Åsa
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    The role of Suppressor of zeste 12 in cell cycle regulationManuscript (Other academic)
    Abstract [en]

    Polycomb group (PcG) proteins control a large amount of target genes and are essential for genomic programming and differentiation. Many members in the PcG family have been shown to be upregulated in different types of cancers. Suppressor of zeste 12 (Su(z)12) is an essential component in PcG silencing and is necessary for histone 3 lysine 27 tri-methylation in vivo. To unravel a possible role of Su(z)12 in cell cycle regulation, we first investigate the localization pattern of Su(z)12 in Drosophila wildtype testes and embryos by immunohistochemical staining. We found that Su(z)12 was dynamically regulated during cell division. Further investigation of the function of Su(z)12 in cell division was done by cell number counting, apoptosis and proliferation marker staining in Su(z)12 somatic knockout clones in wing discs. The conclusion from the small wing phenotype in Su(z)12 knockout wing discs is that Su(z)12 may increase apoptosis and decrease cell proliferation rate.

  • 6.
    Flodbring Larsson, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Karlsson, Richard
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Division of Experimental Cancer Research, Department of Translational Medicine, Clinical Research Centre, Lund University, Malmö, Sweden.
    Sarwar, Martuza
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Miftakhova, Regina R.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wang, Tianyan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Khaja, Azharuddin Sajid Syed
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Semenas, Julius
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Chen, Sa
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Hedblom, Andreas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Division of Experimental Cancer Research, Department of Translational Medicine, Clinical Research Centre, Lund University, Malmö, Sweden.
    Amjad, Ali
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ekström-Holka, Kristina
    Simoulis, Athanasios
    Kumar, Anjani
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Gjörloff Wingren, Anette
    Robinson, Brian
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Mongan, Nigel P.
    Heery, David M.
    Öhlund, Daniel
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Grundström, Thomas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ødum, Niels
    Persson, Jenny L.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Division of Experimental Cancer Research, Department of Translational Medicine, Clinical Research Centre, Lund University, Malmö, Sweden; Department of Biomedical Sciences, Malmö University, Malmö, Sweden.
    FcγRIIIa receptor interacts with androgen receptor and PIP5K1α to promote growth and metastasis of prostate cancer2022In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261Article in journal (Refereed)
    Abstract [en]

    Low-affinity immunoglobulin gamma Fc region receptor III-A (FcγRIIIa) is a cell surface protein that belongs to a family of Fc receptors that facilitate the protective function of the immune system against pathogens. However, the role of FcγRIIIa in prostate cancer (PCa) progression remained unknown. In this study, we found that FcγRIIIa expression was present in PCa cells and its level was significantly higher in metastatic lesions than in primary tumors from the PCa cohort (P = 0.006). PCa patients with an elevated level of FcγRIIIa expression had poorer biochemical recurrence (BCR)-free survival compared with those with lower FcγRIIIa expression, suggesting that FcγRIIIa is of clinical importance in PCa. We demonstrated that overexpression of FcγRIIIa increased the proliferative ability of PCa cell line C4-2 cells, which was accompanied by the upregulation of androgen receptor (AR) and phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Kα), which are the key players in controlling PCa progression. Conversely, targeted inhibition of FcγRIIIa via siRNA-mediated knockdown or using its inhibitory antibody suppressed growth of xenograft PC-3 and PC-3M prostate tumors and reduced distant metastasis in xenograft mouse models. We further showed that elevated expression of AR enhanced FcγRIIIa expression, whereas inhibition of AR activity using enzalutamide led to a significant downregulation of FcγRIIIa protein expression. Similarly, inhibition of PIP5K1α decreased FcγRIIIa expression in PCa cells. FcγRIIIa physically interacted with PIP5K1α and AR via formation of protein-protein complexes, suggesting that FcγRIIIa is functionally associated with AR and PIP5K1α in PCa cells. Our study identified FcγRIIIa as an important factor in promoting PCa growth and invasion. Further, the elevated activation of FcγRIII and AR and PIP5K1α pathways may cooperatively promote PCa growth and invasion. Thus, FcγRIIIa may serve as a potential new target for improved treatment of metastatic and castration-resistant PCa.

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  • 7.
    Fusée, Leila
    et al.
    Inserm U1131, 27 Rue Juliette Dodu, Paris, France.
    Salomao, Norman
    Inserm U1131, 27 Rue Juliette Dodu, Paris, France.
    Ponnuswamy, Anand
    Inserm U1131, 27 Rue Juliette Dodu, Paris, France.
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    López, Ignacio
    Biochemistry-Molecular Biology, Faculty of Science, Universidad de la República, Iguá 4225, Montevideo, Uruguay.
    Chen, Sa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gu, Xiaolian
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Polyzoidis, Stavros
    Department of Neurosurgery, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
    Gnanasundram, Sivakumar Vadivel
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Inserm U1131, 27 Rue Juliette Dodu, Paris, France; RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, Czech Republic.
    The p53 endoplasmic reticulum stress-response pathway evolved in humans but not in mice via PERK-regulated p53 mRNA structures2023In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 30, p. 1072-1081Article in journal (Refereed)
    Abstract [en]

    Cellular stress conditions activate p53-dependent pathways to counteract the inflicted damage. To achieve the required functional diversity, p53 is subjected to numerous post-translational modifications and the expression of isoforms. Little is yet known how p53 has evolved to respond to different stress pathways. The p53 isoform p53/47 (p47 or ΔNp53) is linked to aging and neural degeneration and is expressed in human cells via an alternative cap-independent translation initiation from the 2nd in-frame AUG at codon 40 (+118) during endoplasmic reticulum (ER) stress. Despite an AUG codon in the same location, the mouse p53 mRNA does not express the corresponding isoform in either human or mouse-derived cells. High-throughput in-cell RNA structure probing shows that p47 expression is attributed to PERK kinase-dependent structural alterations in the human p53 mRNA, independently of eIF2α. These structural changes do not take place in murine p53 mRNA. Surprisingly, PERK response elements required for the p47 expression are located downstream of the 2nd AUG. The data show that the human p53 mRNA has evolved to respond to PERK-mediated regulation of mRNA structures in order to control p47 expression. The findings highlight how p53 mRNA co-evolved with the function of the encoded protein to specify p53-activities under different cellular conditions.

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  • 8.
    Gnanasundram, Sivakumar Vadivel
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bonczek, Ondrej
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. RECAMO, Masaryk Memorial Cancer Institute, Zluty Kopec 7, Brno, Czech Republic.
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Chen, Sa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. RECAMO, Masaryk Memorial Cancer Institute, Zluty Kopec 7, Brno, Czech Republic; Inserm UMRS1131, Institut de Genetique Moleculaire, Universite Paris 7, Hopital St Louis, Paris, France; International Centre for Cancer Vaccine Science, University of Gdansk, Gdansk, Poland.
    P53 mRNA metabolism links with the DNA damage response2021In: Genes, E-ISSN 2073-4425, Vol. 12, no 9, article id 1446Article, review/survey (Refereed)
    Abstract [en]

    Human cells are subjected to continuous challenges by different genotoxic stress attacks. DNA damage leads to erroneous mutations, which can alter the function of oncogenes or tumor suppressors, resulting in cancer development. To circumvent this, cells activate the DNA damage response (DDR), which mainly involves cell cycle regulation and DNA repair processes. The tumor suppressor p53 plays a pivotal role in the DDR by halting the cell cycle and facilitating the DNA repair processes. Various pathways and factors participating in the detection and repair of DNA have been described, including scores of RNA-binding proteins (RBPs) and RNAs. It has become increasingly clear that p53’s role is multitasking, and p53 mRNA regulation plays a prominent part in the DDR. This review is aimed at covering the p53 RNA metabolism linked to the DDR and highlights the recent findings.

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  • 9.
    Gnanasundram, Sivakumar Vadivel
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Malbert-Colas, Laurence
    Chen, Sa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fusee, Leila
    Daskalogianni, Chrysoula
    Muller, Petr
    Salomao, Norman
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Inserm UMRS1131, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, Paris, France; RECAMO, Masaryk Memorial Cancer Institute, Zlutykopec 7, Czech Republic; ICCVS, University of Gdańsk, Science, Gdańsk, Poland.
    MDM2's dual mRNA binding domains co-ordinate its oncogenic and tumour suppressor activities2020In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 48, no 12, p. 6775-6787Article in journal (Refereed)
    Abstract [en]

    Cell growth requires a high level of protein synthesis and oncogenic pathways stimulate cell proliferation and ribosome biogenesis. Less is known about how cells respond to dysfunctional mRNA translation and how this feeds back into growth regulatory pathways. The Epstein-Barr virus (EBV)-encoded EBNA1 causes mRNA translation stress in cis that activates PI3Kδ. This leads to the stabilization of MDM2, induces MDM2’s binding to the E2F1 mRNA and promotes E2F1 translation. The MDM2 serine 166 regulates the interaction with the E2F1 mRNA and deletion of MDM2 C-terminal RING domain results in a constitutive E2F1 mRNA binding. Phosphorylation on serine 395 following DNA damage instead regulates p53 mRNA binding to its RING domain and prevents the E2F1 mRNA interaction. The p14Arf tumour suppressor binds MDM2 and in addition to preventing degradation of the p53 protein it also prevents the E2F1 mRNA interaction. The data illustrate how two MDM2 domains selectively bind specific mRNAs in response to cellular conditions to promote, or suppress, cell growth and how p14Arf coordinates MDM2’s activity towards p53 and E2F1. The data also show how EBV via EBNA1-induced mRNA translation stress targets the E2F1 and the MDM2 - p53 pathway.

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  • 10. Haronikova, Lucia
    et al.
    Olivares-Illana, Vanesa
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Karakostis, Konstantinos
    Chen, Sa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic; 4Inserm U1162, Paris, France; ICCVS, University of Gdansk, Science, Gdansk, Poland.
    The p53 mRNA: an integral part of the cellular stress response2019In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 47, no 7, p. 3257-3271Article in journal (Refereed)
    Abstract [en]

    A large number of signalling pathways converge on p53 to induce different cellular stress responses that aim to promote cell cycle arrest and repair or, if the damage is too severe, to induce irreversible senescence or apoptosis. The differentiation of p53 activity towards specific cellular outcomes is tightly regulated via a hierarchical order of post-translational modifications and regulated protein-protein interactions. The mechanisms governing these processes provide a model for how cells optimize the genetic information for maximal diversity. The p53 mRNA also plays a role in this process and this review aims to illustrate how protein and RNA interactions throughout the p53 mRNA in response to different signalling pathways control RNA stability, translation efficiency or alternative initiation of translation. We also describe how a p53 mRNA platform shows riboswitch-like features and controls the rate of p53 synthesis, protein stability and modifications of the nascent p53 protein. A single cancer-derived synonymous mutation disrupts the folding of this platform and prevents p53 activation following DNA damage. The role of the p53 mRNA as a target for signalling pathways illustrates how mRNA sequences have co-evolved with the function of the encoded protein and sheds new light on the information hidden within mRNAs.

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  • 11.
    Karlsson, Richard
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden.
    Larsson, Per
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Miftakhova, Regina R.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Genetics, Kazan Federal University, Kazan, Russia.
    Khaja, Azharuddin Sajid Syed
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sarwar, Martuza
    Semenas, Julius
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden.
    Chen, Sa
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Hedblom, Andreas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden.
    Wang, Tianyan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ekström-Holka, Kristina
    Simoulis, Athanasios
    Kumar, Anjani
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ødum, Nils
    Grundström, Thomas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Persson, Jenny L.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Division of Experimental Cancer Research, Department of Translational Medicine, Lund University, Clinical Research Centre, Malmö, Sweden; Department of Biomedical Sciences, Malmö University, Malmö, Sweden.
    Establishment of Prostate Tumor Growth and Metastasis Is Supported by Bone Marrow Cells and Is Mediated by PIP5K1α Lipid Kinase2020In: Cancers, ISSN 2072-6694, Vol. 12, no 9, article id 2719Article in journal (Refereed)
    Abstract [en]

    Cancer cells facilitate growth and metastasis by using multiple signals from the cancer-associated microenvironment. However, it remains poorly understood whether prostate cancer (PCa) cells may recruit and utilize bone marrow cells for their growth and survival. Furthermore, the regulatory mechanisms underlying interactions between PCa cells and bone marrow cells are obscure. In this study, we isolated bone marrow cells that mainly constituted populations that were positive for CD11b and Gr1 antigens from xenograft PC-3 tumor tissues from athymic nu/nu mice. We found that the tumor-infiltrated cells alone were unable to form tumor spheroids, even with increased amounts and time. By contrast, the tumor-infiltrated cells together with PCa cells formed large numbers of tumor spheroids compared with PCa cells alone. We further utilized xenograft athymic nu/nu mice bearing bone metastatic lesions. We demonstrated that PCa cells were unable to survive and give rise to colony-forming units (CFUs) in media that were used for hematopoietic cell colony-formation unit (CFU) assays. By contrast, PC-3M cells survived when bone marrow cells were present and gave rise to CFUs. Our results showed that PCa cells required bone marrow cells to support their growth and survival and establish bone metastasis in the host environment. We showed that PCa cells that were treated with either siRNA for PIP5K1α or its specific inhibitor, ISA-2011B, were unable to survive and produce tumor spheroids, together with bone marrow cells. Given that the elevated expression of PIP5K1α was specific for PCa cells and was associated with the induced expression of VEGF receptor 2 in PCa cells, our findings suggest that cancer cells may utilize PIP5K1α-mediated receptor signaling to recruit growth factors and ligands from the bone marrow-derived cells. Taken together, our study suggests a new mechanism that enables PCa cells to gain proliferative and invasive advantages within their associated host microenvironment. Therapeutic interventions using PIP5K1α inhibitors may not only inhibit tumor invasion and metastasis but also enhance the host immune system.

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  • 12.
    Larsson, Anna
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Tegeling, Erik
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Chen, Sa
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Lu, C-M
    Stief, A
    Rasmuson-Lestander, Åsa
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Investigation of the two isoforms of SU(Z)12 shows difference in expressionand interaction in vitro with the core components of PRC2Manuscript (preprint) (Other academic)
  • 13.
    Toh, Eric
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Baryalai, Palwasha
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nadeem, Aftab
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Aung, Kyaw Min
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Chen, Sa
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Persson, Karina
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Persson, Jenny L.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bacterial protein MakA causes suppression of tumour cell proliferation via inhibition of PIP5K1α/Akt signalling2022In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 13, no 12, article id 1024Article in journal (Refereed)
    Abstract [en]

    Recently, we demonstrated that a novel bacterial cytotoxin, the protein MakA which is released by Vibrio cholerae, is a virulence factor, causing killing of Caenorhabditis elegans when the worms are grazing on the bacteria. Studies with mammalian cell cultures in vitro indicated that MakA could affect eukaryotic cell signalling pathways involved in lipid biosynthesis. MakA treatment of colon cancer cells in vitro caused inhibition of growth and loss of cell viability. These findings prompted us to investigate possible signalling pathways that could be targets of the MakA-mediated inhibition of tumour cell proliferation. Initial in vivo studies with MakA producing V. cholerae and C. elegans suggested that the MakA protein might target the PIP5K1α phospholipid-signalling pathway in the worms. Intriguingly, MakA was then found to inhibit the PIP5K1α lipid-signalling pathway in cancer cells, resulting in a decrease in PIP5K1α and pAkt expression. Further analyses revealed that MakA inhibited cyclin-dependent kinase 1 (CDK1) and induced p27 expression, resulting in G2/M cell cycle arrest. Moreover, MakA induced downregulation of Ki67 and cyclin D1, which led to inhibition of cell proliferation. This is the first report about a bacterial protein that may target signalling involving the cancer cell lipid modulator PIP5K1α in colon cancer cells, implying an anti-cancer effect.

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  • 14. Uhrik, Lukas
    et al.
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Haronikova, Lucia
    Medina-Medina, Ixaura
    Rebolloso-Gomez, Yolanda
    Chen, Sa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Vojtesek, Borivoj
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hernychova, Lenka
    Olivares-Illana, Vanesa
    Allosteric changes in HDM2 by the ATM phosphomimetic S395D mutation: implications on HDM2 function2019In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 476, p. 3401-3411Article in journal (Refereed)
    Abstract [en]

    Allosteric changes imposed by post-translational modifications regulate and differentiate the functions of proteins with intrinsic disorder regions. HDM2 is a hub protein with a large interactome and with different cellular functions. It is best known for its regulation of the p53 tumour suppressor. Under normal cellular conditions, HDM2 ubiquitinates and degrades p53 by the 26S proteasome but after DNA damage, HDM2 switches from a negative to a positive regulator of p53 by binding to p53 mRNA to promote translation of the p53 mRNA. This change in activity is governed by the ataxia telangiectasia mutated kinase via phosphorylation on serine 395 and is mimicked by the S395D phosphomimetic mutant. Here we have used different approaches to show that this event is accompanied by a specific change in the HDM2 structure that affects the HDM2 interactome, such as the N-termini HDM2-p53 protein-protein interaction. These data will give a better understanding of how HDM2 switches from a negative to a positive regulator of p53 and gain new insights into the control of the HDM2 structure and its interactome under different cellular conditions and help identify interphases as potential targets for new drug developments.

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  • 15.
    Wang, Tianyan
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sarwar, Martuza
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Whitchurch, Jonathan B.
    School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
    Collins, Hilary M.
    School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
    Green, Tami
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Semenas, Julius
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Amjad, Ali
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Roberts, Christopher J.
    School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
    Morris, Ryan D.
    School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
    Hubert, Madlen
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Department of Pharmacy, Uppsala University, Uppsala, Sweden.
    Chen, Sa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    El-Schich, Zahra
    Department of Biomedical Science, Malmö University, Malmö, Sweden.
    Wingren, Anette G.
    Department of Biomedical Science, Malmö University, Malmö, Sweden.
    Grundström, Thomas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Mongan, Nigel P.
    School of Veterinary Medicine and Science, University of Nottingham, Nottingham, United Kingdom; Department of Pharmacology, Weill Cornell Medicine, New York, NY, United States.
    Gunhaga, Lena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Heery, David M.
    School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
    Persson, Jenny L.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Biomedical Science, Malmö University, Malmö, Sweden; Department of Translational Medicine, Lund University, Clinical Research Centre in Malmö, Malmö, Sweden.
    PIP5K1α is Required for Promoting Tumor Progression in Castration-Resistant Prostate Cancer2022In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 10, article id 798590Article in journal (Refereed)
    Abstract [en]

    PIP5K1α has emerged as a promising drug target for the treatment of castration-resistant prostate cancer (CRPC), as it acts upstream of the PI3K/AKT signaling pathway to promote prostate cancer (PCa) growth, survival and invasion. However, little is known of the molecular actions of PIP5K1α in this process. Here, we show that siRNA-mediated knockdown of PIP5K1α and blockade of PIP5K1α action using its small molecule inhibitor ISA-2011B suppress growth and invasion of CRPC cells. We demonstrate that targeted deletion of the N-terminal domain of PIP5K1α in CRPC cells results in reduced growth and migratory ability of cancer cells. Further, the xenograft tumors lacking the N-terminal domain of PIP5K1α exhibited reduced tumor growth and aggressiveness in xenograft mice as compared to that of controls. The N-terminal domain of PIP5K1α is required for regulation of mRNA expression and protein stability of PIP5K1α. This suggests that the expression and oncogenic activity of PIP5K1α are in part dependent on its N-terminal domain. We further show that PIP5K1α acts as an upstream regulator of the androgen receptor (AR) and AR target genes including CDK1 and MMP9 that are key factors promoting growth, survival and invasion of PCa cells. ISA-2011B exhibited a significant inhibitory effect on AR target genes including CDK1 and MMP9 in CRPC cells with wild-type PIP5K1α and in CRPC cells lacking the N-terminal domain of PIP5K1α. These results indicate that the growth of PIP5K1α-dependent tumors is in part dependent on the integrity of the N-terminal sequence of this kinase. Our study identifies a novel functional mechanism involving PIP5K1α, confirming that PIP5K1α is an intriguing target for cancer treatment, especially for treatment of CRPC.

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  • 16.
    Zheng, Alice J L
    et al.
    Inserm UMRS 1131, Institut de Génétique Moléculaire, Université de Paris, Hôpital St. Louis, Paris, France.
    Thermou, Aikaterini
    Inserm UMRS 1131, Institut de Génétique Moléculaire, Université de Paris, Hôpital St. Louis, Paris, France; University of Gdańsk, Science, ul. Wita Stwosza 63, 80-308 Gdańsk, Poland.
    Daskalogianni, Chrysoula
    Inserm UMRS 1131, Institut de Génétique Moléculaire, Université de Paris, Hôpital St. Louis, Paris, France; University of Gdańsk, Science, ul. Wita Stwosza 63, 80-308 Gdańsk, Poland.
    Malbert-Colas, Laurence
    Inserm UMRS 1131, Institut de Génétique Moléculaire, Université de Paris, Hôpital St. Louis, Paris, France.
    Karakostis, Konstantinos
    Inserm UMRS 1131, Institut de Génétique Moléculaire, Université de Paris, Hôpital St. Louis, Paris, France.
    Le Sénéchal, Ronan
    Inserm UMR 1078, Université de Bretagne Occidentale (UBO), Etablissement Français du Sang (EFS) Bretagne, CHRU Brest, Brest, France.
    Trang Dinh, Van
    Inserm UMR 1078, Université de Bretagne Occidentale (UBO), Etablissement Français du Sang (EFS) Bretagne, CHRU Brest, Brest, France.
    Tovar Fernandez, Maria C.
    Inserm UMRS 1131, Institut de Génétique Moléculaire, Université de Paris, Hôpital St. Louis, Paris, France; University of Gdańsk, Science, ul. Wita Stwosza 63, 80-308 Gdańsk, Poland.
    Apcher, Sébastien
    Institut Gustave Roussy, Université Paris Sud, Unité 1015 département d'immunologie, 114, rue Edouard Vaillant, 94805 Villejuif, France.
    Chen, Sa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Blondel, Marc
    Inserm UMR 1078, Université de Bretagne Occidentale (UBO), Etablissement Français du Sang (EFS) Bretagne, CHRU Brest, Brest, France.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Inserm UMRS 1131, Institut de Génétique Moléculaire, Université de Paris, Hôpital St. Louis, Paris, France; RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, Czech Republic.
    The nascent polypeptide-associated complex (NAC) controls translation initiation in cis by recruiting nucleolin to the encoding mRNA2022In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 50, no 17, p. 10110-10122Article in journal (Refereed)
    Abstract [en]

    Protein aggregates and abnormal proteins are toxic and associated with neurodegenerative diseases. There are several mechanisms to help cells get rid of aggregates but little is known on how cells prevent aggregate-prone proteins from being synthesised. The EBNA1 of the Epstein-Barr virus (EBV) evades the immune system by suppressing its own mRNA translation initiation in order to minimize the production of antigenic peptides for the major histocompatibility (MHC) class I pathway. Here we show that the emerging peptide of the disordered glycine-alanine repeat (GAr) within EBNA1 dislodges the nascent polypeptide-associated complex (NAC) from the ribosome. This results in the recruitment of nucleolin to the GAr-encoding mRNA and suppression of mRNA translation initiation in cis. Suppressing NAC alpha (NACA) expression prevents nucleolin from binding to the GAr mRNA and overcomes GAr-mediated translation inhibition. Taken together, these observations suggest that EBNA1 exploits a nascent protein quality control pathway to regulate its own rate of synthesis that is based on sensing the nascent GAr peptide by NAC followed by the recruitment of nucleolin to the GAr-encoding RNA sequence.

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