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  • 1. Fulton, Joel
    et al.
    Mazumder, Bismoy
    Whitchurch, Jonathan B.
    Monteiro, Cintia J.
    Collins, Hilary M.
    Chan, Chun M.
    Clemente, Maria P.
    Hernandez-Quiles, Miguel
    Stewart, Elizabeth A.
    Amoaku, Winfried M.
    Moran, Paula M.
    Mongan, Nigel P.
    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.
    Ali, Simak
    Heery, David M.
    Heterodimers of photoreceptor-specific nuclear receptor (PNR/NR2E3) and peroxisome proliferator-activated receptor-gamma (PPAR gamma) are disrupted by retinal disease-associated mutations2017In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 8, e2677Article in journal (Refereed)
    Abstract [en]

    Photoreceptor-specific nuclear receptor (PNR/NR2E3) and Tailless homolog (TLX/NR2E1) are human orthologs of the NR2E group, a subgroup of phylogenetically related members of the nuclear receptor (NR) superfamily of transcription factors. We assessed the ability of these NRs to form heterodimers with other members of the human NRs representing all major subgroups. The TLX ligand-binding domain (LBD) did not appear to form homodimers or interact directly with any other NR tested. The PNR LBD was able to form homodimers, but also exhibited robust interactions with the LBDs of peroxisome proliferator-activated receptor-gamma (PPAR gamma)/NR1C3 and thyroid hormone receptor b (TRb) TR beta/NR1A2. The binding of PNR to PPAR. was specific for this paralog, as no interaction was observed with the LBDs of PPAR alpha/NR1C1 or PPAR delta/NR1C2. In support of these findings, PPAR. and PNR were found to be co-expressed in human retinal tissue extracts and could be co-immunoprecipitated as a native complex. Selected sequence variants in the PNR LBD associated with human retinopathies, or a mutation in the dimerization region of PPAR. LBD associated with familial partial lipodystrophy type 3, were found to disrupt PNR/PPAR gamma complex formation. Wild-type PNR, but not a PNR309G mutant, was able to repress PPAR gamma-mediated transcription in reporter assays. In summary, our results reveal novel heterodimer interactions in the NR superfamily, suggesting previously unknown functional interactions of PNR with PPAR. and TR beta that have potential importance in retinal development and disease.

  • 2. Kunkl, Martina
    et al.
    Porciello, Nicla
    Mastrogiovanni, Marta
    Capuano, Cristina
    Lucantoni, Federica
    Moretti, Chiara
    Persson, Jenny L.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Division of Experimental Cancer Research, Department of Laboratory Medicine, Clinical Research Center, Lund University, Malmö, Sweden.
    Galandrini, Ricciarda
    Buzzetti, Raffaella
    Tuosto, Loretta
    ISA-2011B, a Phosphatidylinositol 4-Phosphate 5-Kinase alpha Inhibitor, impairs CD28-Dependent Costimulatory and Pro-inflammatory Signals in Human T Lymphocytes2017In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, 502Article in journal (Refereed)
    Abstract [en]

    Phosphatidylinositol 4,5-biphosphate (PIP2) is a membrane phospholipid that controls the activity of several proteins regulating cytoskeleton reorganization, cytokine gene expression, T cell survival, proliferation, and differentiation. Phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) are the main enzymes involved in PIP2 biosynthesis by phosphorylating phosphatidylinositol 4-monophosphate (PI4P) at the D5 position of the inositol ring. In human T lymphocytes, we recently found that CD28 costimulatory molecule is pivotal for PIP2 turnover by recruiting and activating PIP5K alpha. We also found that PIP5K alpha is the main regulator of both CD28 costimulatory signals integrating those delivered by TCR as well as CD28 autonomous signals regulating the expression of pro-inflammatory genes. Given emerging studies linking alterations of PIP2 metabolism to immune-based diseases, PIP5Ka may represent a promising target to modulate immunity and inflammation. Herewith, we characterized a recently discovered inhibitor of PIP5K alpha, ISA-2011B, for its inhibitory effects on T lymphocyte functions. We found that the inhibition of PIP5K alpha lipid-kinase activity by ISA-2011B significantly impaired CD28 costimulatory signals necessary for TCR-mediated Ca2+ influx, NF-AT transcriptional activity, and IL-2 gene expression as well as CD28 autonomous signals regulating the activation of NF-kappa B and the transcription of pro-inflammatory cytokine and chemokine genes. Moreover, our data on the inhibitory effects of ISA-2011B on CD28-mediated upregulation of inflammatory cytokines related to Th17 cell phenotype in type 1 diabetes patients suggest ISA-2011B as a promising anti-inflammatory drug.

  • 3. Metzler, Veronika M.
    et al.
    de Brot, Simone
    Robinson, Robert S.
    Jeyapalan, Jennie N.
    Rakha, Emad
    Walton, Thomas
    Gardner, David S.
    Lund, Emma F.
    Whitchurch, Jonathan
    Haigh, Daisy
    Lochray, Jack M.
    Robinson, Brian D.
    Allegrucci, Cinzia
    Fray, Rupert G.
    Persson, Jenny L.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Translational Medicine, Lund University, Malmo, Sweden.
    Odum, Niels
    Miftakhova, Regina R.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Kazan Federal University, Kazan, Republic of Tatarstan, Russian Federation.
    Rizvanov, Albert A.
    Hughes, Ieuan A.
    Tadokoro-Cuccaro, Rieko
    Heery, David M.
    Rutland, Catrin S.
    Mongan, Nigel P.
    Androgen dependent mechanisms of pro-angiogenic networks in placental and tumor development2017In: Placenta, ISSN 0143-4004, E-ISSN 1532-3102, Vol. 56, 79-85 p.Article in journal (Refereed)
    Abstract [en]

    The placenta and tumors share important characteristics, including a requirement to establish effective angiogenesis. In the case of the placenta, optimal angiogenesis is required to sustain the blood flow required to maintain a successful pregnancy, whereas in tumors establishing new blood supplies is considered a key step in supporting metastases. Therefore the development of novel angiogenesis inhibitors has been an area of active research in oncology. A subset of the molecular processes regulating angiogenesis are well understood in the context of both early placentation and tumorigenesis. In this review we focus on the well-established role of androgen regulation of angiogenesis in cancer and relate these mechanisms to placental angiogenesis. The physiological actions of androgens are mediated by the androgen receptor (AR), a ligand dependent transcription factor. Androgens and the AR are essential for normal male embryonic development, puberty and lifelong health. Defects in androgen signalling are associated with a diverse range of clinical disorders in men and women including disorders of sex development (DSD), polycystic ovary syndrome in women and many cancers. We summarize the diverse molecular mechanisms of androgen regulation of angiogenesis and infer the potential significance of these pathways to normal and pathogenic placental function. Finally, we offer potential research applications of androgen-targeting molecules developed to treat cancer as investigative tools to help further delineate the role of androgen signalling in placental function and maternal and offspring health in animal models.

  • 4. Sarwar, Martuza
    et al.
    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.
    Miftakhova, Regina
    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 Genetics, Kazan Federal University, Kazan, Russia.
    Simoulis, Athanasios
    Robinson, Brian
    Wingren, Anette Gjorloff
    Mongan, Nigel P.
    Heery, David M.
    Johnsson, Heather
    Abrahamsson, Per-Anders
    Dizeyi, Nishtman
    Luo, Jun
    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.
    Targeted suppression of AR-V7 using PIP5K1 alpha inhibitor overcomes enzalutamide resistance in prostate cancer cells2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 39, 63065-63081 p.Article in journal (Refereed)
    Abstract [en]

    One mechanism of resistance of prostate cancer (PCa) to enzalutamide (MDV3100) treatment is the increased expression of AR variants lacking the ligand binding-domain, the best characterized of which is AR-V7. We have previously reported that Phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5K alpha), is a lipid kinase that links to CDK1 and AR pathways. The discovery of PIP5K alpha inhibitor highlight the potential of PIP5K1 alpha as a drug target in PCa. In this study, we show that AR-V7 expression positively correlates with PIP5K1 alpha in tumor specimens from PCa patients. Overexpression of AR-V7 increases PIP5K1 alpha, promotes rapid growth of PCa in xenograft mice, whereas inhibition of PIP5K1 alpha by its inhibitor ISA-2011B suppresses the growth and invasiveness of xenograft tumors overexpressing AR-V7. PIP5K1 alpha is a key co-factor for both AR-V7 and AR, which are present as protein-protein complexes predominantly in the nucleus of PCa cells. In addition, PIP5K1 alpha and CDK1 influence AR-V7 expression also through AKT-associated mechanism dependent on PTEN-status. ISA-2011B disrupts protein stabilization of AR-V7 which is dependent on PIP5K1 alpha, leading to suppression of invasive growth of AR-V7-high tumors in xenograft mice. Our study suggests that combination of enzalutamide and PIP5K1 alpha may have a significant impact on refining therapeutic strategies to circumvent resistance to antiandrogen therapies.

  • 5. Shah, Mansi
    et al.
    Cardenas, Ryan
    Wang, Belinda
    Persson, Jenny
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Mongan, Nigel P.
    Grabowska, Anna
    Allegrucci, Cinzia
    HOXC8 regulates self-renewal, differentiation and transformation of breast cancer stem cells2017In: Molecular Cancer, ISSN 1476-4598, E-ISSN 1476-4598, Vol. 16, 38Article in journal (Refereed)
    Abstract [en]

    Background: Homeobox genes are master regulators of cell fate during embryonic development and their expression is altered in cancer. By regulating the balance between cell proliferation and differentiation, they maintain homeostasis of normal tissues. Here, we screened the expression of homeobox genes in mammary stem cells to establish their role in stem cells transformation in breast cancer. Methods: Using a Homeobox Genes PCR array, we screened 83 homeobox genes in normal cancer breast stem/progenitor cells isolated by flow cytometry. The candidate gene HOXC8 epigenetic regulation was studied by DNA methylation and miRNA expression analyses. Self-renewal and differentiation of HOXC8-overexpressing or knockdown cells were assessed by flow cytometry and mammosphere, 3D matrigel and soft agar assays. Clinical relevance of in vitro findings were validated by bioinformatics analysis of patient datasets from TCGA and METABRIC studies. Results: In this study we demonstrate altered expression of homeobox genes in breast cancer stem/progenitor cells. HOXC8 was consistently downregulated in stem/progenitor cells of all breast molecular subtypes, thus representing an interesting tumour suppressor candidate. We show that downregulated expression of HOXC8 is associated with DNA methylation at the gene promoter and expression of miR196 family members. Functional studies demonstrated that HOXC8 gain of function induces a decrease in the CD44(+)/CD24(-/low) cancer stem cell population and proportion of chemoresistant cells, with a concomitant increase in CD24(+) differentiated cells. Increased HOXC8 levels also decrease the ability of cancer cells to form mammospheres and to grow in anchorage-independent conditions. Furthermore, loss of HOXC8 in non-tumorigenic mammary epithelial cells expands the cancer stem/progenitor cells pool, increases stem cell self-renewal, prevents differentiation induced by retinoic acid and induces a transformed phenotype. Conclusions: Taken together, our study points to an important role of homeobox genes in breast cancer stem/progenitor cell function and establishes HOXC8 as a suppressor of stemness and transformation in the mammary gland lineage.

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  • Other locale
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