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Publications (10 of 26) Show all publications
Nahálková, J. (2016). The protein-interaction network with functional roles in tumorigenesis, neurodegeneration, and aging. Molecular and Cellular Biochemistry, 423(1-2), 187-196
Open this publication in new window or tab >>The protein-interaction network with functional roles in tumorigenesis, neurodegeneration, and aging
2016 (English)In: Molecular and Cellular Biochemistry, ISSN 0300-8177, E-ISSN 1573-4919, Vol. 423, no 1-2, p. 187-196Article, review/survey (Refereed) Published
Abstract [en]

The present review summarizes the knowledge about a protein-interaction network, which includes proteins with significant functions in the mechanisms of aging and age-related diseases. All the detected interacting proteins TPPII, p53, MYBBP1A, CDK2 and SIRT7, SIRT6, and CD147 are suitable for the development of antitumor therapeutics and treatments for diseases of aging. TPPII and SIRT6 directly affect glucose metabolism which drive malignant growth. In addition, SIRT6 activators are attractive candidates for Alzheimer's disease (AD) due to the protection effect of SIRT6 overexpression from DNA damage. TPPII activity exhibits a decreasing effect on mTOR signaling, and its requirement for the degradation of A beta peptides in the human fibroblasts suggests that it has dual functions in tumorigenesis and AD-related pathology. Likewise, the direct promotion of the invasiveness of breast epithelial cells and the contribution to the A beta degradation by stimulating the matrix metalloproteinases production suggest a double functional role for CD147. An association of the partial portion of cellular CD147 to gamma-secretase further supports the functional relation to AD pathology. The animal and cellular models with downregulated or knockout TPPII, p53, SIRT6, SIRT7, and MYBBP1A expression levels illustrate similar functions of the interacting proteins. They demonstrate similar effects on the length of life span, premature aging, and lipid metabolism. The presented protein-interaction network is relevant to the discoveries of the mechanisms of tumorigenesis, aging, and neurodegeneration.

Keywords
TPPII, P53, MYBBP1A, SIRT7, SIRT6, CD147
National Category
Cell Biology
Identifiers
urn:nbn:se:uu:diva-308883 (URN)10.1007/s11010-016-2836-5 (DOI)000387365600018 ()27699588 (PubMedID)
Available from: 2016-12-01 Created: 2016-12-01 Last updated: 2017-11-29Bibliographically approved
Nahálková, J. & Tomkinson, B. (2014). TPPII, MYBBP1A and CDK2 form a protein–protein interaction network. Archives of Biochemistry and Biophysics, 564, 128-135
Open this publication in new window or tab >>TPPII, MYBBP1A and CDK2 form a protein–protein interaction network
2014 (English)In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 564, p. 128-135Article in journal (Refereed) Published
Abstract [en]

Tripeptidyl-peptidase II (TPPII) is an aminopeptidase with suggested regulatory effects on cell cycle, apoptosis and senescence. A protein–protein interaction study revealed that TPPII physically interacts with the tumor suppressor MYBBP1A and the cell cycle regulator protein CDK2. Mutual protein–protein interaction was detected between MYBBP1A and CDK2 as well. In situ Proximity Ligation Assay (PLA) using HEK293 cells overexpressing TPPII forming highly enzymatically active oligomeric complexes showed that the cytoplasmic interaction frequency of TPPII with MYBBP1A increased with the protein expression of TPPII and using serum-free cell growth conditions. A specific reversible inhibitor of TPPII, butabindide, suppressed the cytoplasmic interactions of TPPII and MYBBP1A both in control HEK293 and the cells overexpressing murine TPPII. The interaction of MYBBP1A with CDK2 was confirmed by in situPLA in two different mammalian cell lines. Functional link between TPPII and MYBBP1A has been verified by gene expression study during anoikis, where overexpression of TPP II decreased mRNA expression level of MYBBP1A at the cell detachment conditions. All three interacting proteins TPPII, MYBBP1A and CDK2 have been previously implicated in the research for development of tumor-suppressing agents. This is the first report presenting mutual protein–protein interaction network of these proteins.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
TPPII, MYBBP1A, CDK2, Cell cycle, Apoptosis
National Category
Biochemistry and Molecular Biology
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:uu:diva-235245 (URN)10.1016/j.abb.2014.09.017 (DOI)000346222600015 ()25303791 (PubMedID)
Available from: 2014-10-30 Created: 2014-10-30 Last updated: 2017-12-05Bibliographically approved
Nahalkova, J., Volkmann, I., Aoki, M., Winblad, B., Bogdanovic, N., Tjernberg, L. O. & Behbahani, H. (2010). CD147, a gamma-secretase associated protein is upregulated in Alzheimer's disease brain and its cellular trafficking is affected by presenilin-2. Neurochemistry International, 56(1), 67-76
Open this publication in new window or tab >>CD147, a gamma-secretase associated protein is upregulated in Alzheimer's disease brain and its cellular trafficking is affected by presenilin-2
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2010 (English)In: Neurochemistry International, ISSN 0197-0186, E-ISSN 1872-9754, Vol. 56, no 1, p. 67-76Article in journal (Refereed) Published
Abstract [en]

gamma-Secretase activity has been extensively investigated due to its role in Alzheimer's disease. Here, we studied the association of CD147, a transmembrane glycoprotein belonging to the immunoglobulin family, with gamma-secretase and its expression in Alzheimer's disease and control tissues. Subcellular fractionation of postmitochondrial supernatant from Fat brain on step iodixanol gradient in combination with co-immunoprecipitation using an anti-nicastrin antibody showed association of limited amount of CD147 to gamma-secretase. By immunoblotting of postnuclear pellets from Alzheimer's disease and control human brain tissues we showed that CD147 with molecular weight 75 kDa is upregulated in frontal cortex and thalamus of the Alzheimer's disease brains. Immunohistochemistry of brain tissues from Alzheimer's disease and control revealed specific Upregulation of CD147 in neurons, axons and capillaries of Alzheimer's disease frontal cortex and thalamus. The effect of presenilin-1 and -2, which are the catalytic subunits of gamma-secretase, on CD147 expression and subcellular localization was analyzed by confocal microscopy in combination with flow cytometry and showed that PS2 affected the subcellular localization of CD147 in Mouse embryonic fibroblast cells. We suggest that a small fraction of CD147 present in the brain is associated with the gamma-secretase, and can be involved in mechanisms dysregulated in Alzheimer's disease brain.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-216603 (URN)10.1016/j.neuint.2009.09.003 (DOI)000275593700010 ()
Available from: 2014-01-23 Created: 2014-01-23 Last updated: 2018-01-11Bibliographically approved
Frykman, S., Hur, J.-Y., Frånberg, J., Aoki, M., Winblad, B., Nahalkova, J., . . . Tjernberg, L. O. (2010). Synaptic and Endosomal Localization of Active gamma-Secretase in Rat Brain. PLoS ONE, 5(1), e8948
Open this publication in new window or tab >>Synaptic and Endosomal Localization of Active gamma-Secretase in Rat Brain
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2010 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 1, p. e8948-Article in journal (Refereed) Published
Abstract [en]

Background

A key player in the development of Alzheimer's disease (AD) is the gamma-secretase complex consisting of at least four components: presenilin, nicastrin, Aph-1 and Pen-2. gamma-Secretase is crucial for the generation of the neurotoxic amyloid beta-peptide (A beta) but also takes part in the processing of many other substrates. In cell lines, active gamma-secretase has been found to localize primarily to the Golgi apparatus, endosomes and plasma membranes. However, no thorough studies have been performed to show the subcellular localization of the active gamma-secretase in the affected organ of AD, namely the brain.

Principal Findings

We show by subcellular fractionation of rat brain that high gamma-secretase activity, as assessed by production of A beta 40, is present in an endosome-and plasma membrane-enriched fraction of an iodixanol gradient. We also prepared crude synaptic vesicles as well as synaptic membranes and both fractions showed high A beta 40 production and contained high amounts of the gamma-secretase components. Further purification of the synaptic vesicles verified the presence of the gamma-secretase components in these compartments. The localization of an active gamma-secretase in synapses and endosomes was confirmed in rat brain sections and neuronal cultures by using a biotinylated gamma-secretase inhibitor together with confocal microscopy.

Significance

The information about the subcellular localization of gamma-secretase in brain is important for the understanding of the molecular mechanisms of AD. Furthermore, the identified fractions can be used as sources for highly active gamma-secretase.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-216602 (URN)10.1371/journal.pone.0008948 (DOI)000274138000023 ()
Available from: 2014-01-23 Created: 2014-01-23 Last updated: 2018-01-11Bibliographically approved
Adomas, A., Heller, G., Olson, Å., Osborne, J., Karlsson, M., Nahalkova, J., . . . Asiegbu, F. O. (2008). Comparative analysis of transcript abundance in Pinus sylvestris after challenge with a saprotrophic, pathogenic or mutualistic fungus. Tree Physiology, 28(6), 885-897
Open this publication in new window or tab >>Comparative analysis of transcript abundance in Pinus sylvestris after challenge with a saprotrophic, pathogenic or mutualistic fungus
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2008 (English)In: Tree Physiology, ISSN 0829-318X, E-ISSN 1758-4469, Vol. 28, no 6, p. 885-897Article in journal (Refereed) Published
Abstract [en]

To investigate functional differences in the recognition and response mechanisms of conifer roots to fungi with different trophic strategies, Pinus sylvestris L. was challenged with a saprotrophic fungus Trichoderma aureoviride Rifai. The results were compared with separate studies investigating pine interactions with a pathogen, Heterobasidion annosum (Fr.) Bref. sensu stricto and an ectomycorrhizal symbiont, Laccaria bicolor Maire (Orton). Global changes in the expression of 2109 conifer genes were assayed 1, 5 and 15 days after inoculation. Gene expression data from a cDNA microarray were analyzed by the 2-interconnected mixed linear model statistical approach. The total number of genes differentially expressed compared with the uninfected control was similar after challenge with the pathogen and the ectomycorrhizal symbiont, but the number of differentially expressed genes increased over time, for H. annosum, and decreased for L. bicolor. Inoculation of pine roots with T aureoviride resulted overall in a much lower number of genes with changed transcript levels compared with inoculation with H. annosum or L. bicolor. Functional classification of the differentially expressed genes revealed that the ectomycorrhizal fungus triggered transient induction of defence-related genes. The response and induction of defence against the pathogen was delayed and the magnitude increased over time. Thus, there were specific transcriptional responses depending on whether the conifer roots were challenged with mutualistic, saprotrophic or pathogenic fungi. This suggests that pine trees are able to recognize diverse fungal species and specifically distinguish whether they are pathogenic, neutral or beneficial microbial agents.

National Category
Agricultural Science, Forestry and Fisheries
Identifiers
urn:nbn:se:uu:diva-216605 (URN)10.1093/treephys/28.6.885 (DOI)000256711500007 ()
Available from: 2014-01-23 Created: 2014-01-23 Last updated: 2017-12-06Bibliographically approved
Nahalkova, J., Fatehi, J., Olivain, C. & Alabouvette, C. (2008). Tomato root colonization by fluorescent-tagged pathogenic and protective strains of Fusarium oxysporum in hydroponic culture differs from root colonization in soil. FEMS Microbiology Letters, 286(2), 152-157
Open this publication in new window or tab >>Tomato root colonization by fluorescent-tagged pathogenic and protective strains of Fusarium oxysporum in hydroponic culture differs from root colonization in soil
2008 (English)In: FEMS Microbiology Letters, ISSN 0378-1097, E-ISSN 1574-6968, Vol. 286, no 2, p. 152-157Article in journal (Refereed) Published
Abstract [en]

The colonization process of tomato roots inoculated separately or/and simultaneously by a pathogenic Fusarium oxysporum f. sp. lycopersici strain Fol8 and the protective F. oxysporum strain Fo47, genetically tagged with the red and green fluorescent protein genes, respectively, was studied in a hydroponic culture. Plants were coinoculated with Fol8 and Fo47 at two conidial concentration ratios of 1/1 and 1/100, in which biological control was not effective or effective, respectively. First observation of fungi on root was possible 48 h after inoculation at a high inoculum level and 5 days post inoculation at the lower concentration of inoculum. The pattern of root colonization was similar for both strains with the initial development of hyphal network on the upper part of taproot, followed by the growth of hyphae towards the elongation zone, lateral roots and root apices. Finally, the whole elongation zone and root apex were invaded by both strains but no specific infection sites were observed. When coinoculated, both strains could grow very closely or even at the same spot on the root surface. At the nonprotective ratio, Fol8 was the successful colonizer, but application of Fo47 at a concentration 100 times > , Fol8 delayed vessel colonization by the pathogen.

Keywords
Fusarium oxysporum f. sp lycopersici, Fo47, Lycopersicon esculentum
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-109148 (URN)10.1111/j.1574-6968.2008.01241.x (DOI)000258402200002 ()
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2017-12-13Bibliographically approved
Olivain, C., Humbert, C., Nahalkova, J., Fatehi, J., L'Haridon, F. & Alabouvette, C. (2006). Colonization of tomato root by pathogenic and nonpathogenic Fusarium oxysporum strains inoculated together and separately into the soil. Applied and Environmental Microbiology, 72(2), 1523-1531
Open this publication in new window or tab >>Colonization of tomato root by pathogenic and nonpathogenic Fusarium oxysporum strains inoculated together and separately into the soil
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2006 (English)In: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 72, no 2, p. 1523-1531Article in journal (Refereed) Published
Abstract [en]

In soil, fungal colonization of plant roots has been traditionally studied by indirect methods such as microbial isolation that do not enable direct observation of infection sites or of interactions between fungal pathogens and their antagonists. Confocal laser scanning microscopy was used to visualize the colonization of tomato roots in heat-treated soil and to observe the interactions between a nonpathogenic strain, Fo47, and a pathogenic strain, Fo18, inoculated onto tomato roots in soil. When inoculated separately, both fungi colonized the entire root surface, with the exception of the apical zone. When both strains were introduced together, they both colonized the root surface and were observed at the same locations. When Fo47 was introduced at a higher concentration than Fo18, it colonized much of the root surface, but hyphae of Fo18 could still be observed at the same location on the root. There was no exclusion of the pathogenic strain by the presence of the nonpathogenic strain. These results are not consistent with the hypothesis that specific infection sites exist on the root for Fusarium oxysporum and instead support the hypothesis that competition occurs for nutrients rather than for infection sites.

National Category
Agricultural Biotechnology
Identifiers
urn:nbn:se:uu:diva-216606 (URN)10.1128/AEM.72.2.1523-1531.2006 (DOI)000235353100070 ()
Available from: 2014-01-23 Created: 2014-01-23 Last updated: 2017-12-06
Asiegbu, F. O., Nahalkova, J. & Li, G. S. (2005). Pathogen-inducible cDNAs from the interaction of the root rot fungus Heterobasidion annosum with Scots pine (Pinus sylvestris L.). Plant Science, 168(2), 365-372
Open this publication in new window or tab >>Pathogen-inducible cDNAs from the interaction of the root rot fungus Heterobasidion annosum with Scots pine (Pinus sylvestris L.)
2005 (English)In: Plant Science, ISSN 0168-9452, E-ISSN 1873-2259, Vol. 168, no 2, p. 365-372Article in journal (Refereed) Published
Abstract [en]

Subtractive hybridization was used to select cDNAs representing genes that are differentially expressed during interaction of the necrotroph Heterobasidion annosum and its conifer host (Pinus sylvestris). We obtained 966 ESTs from the subtraction cDNA library, which included 509 singletons and 147 contigs. The sequences of 492 clones (51%) significantly matched National Centre for Biotechnology Information Database entries. Four hundred and seventy-four ESTs (49%) had not been previously described. The ESTs with moderate to high similarity scores based on BlastX were organized into categories based on their putative function. Among the genes identified, 16% were associated with metabolism and other cellular functions, 14% with cell rescue and defence and 39% were classified as unknown. Seven of the genes shared significant homology to fungal genes. A cDNA encoding an antimicrobial peptide (AMP) was the most abundant transcript representing 2% of the total sequenced clones. The expression pattern of five ESTs (peroxidase, anti-microbial peptide, resistance gene analogue, unknown protein, thaumatin) were analysed by virtual Northern blot, and confirmed elevated levels of the gene transcripts upon pathogen infection. These ESTs provide insight into the host-pathogen interaction and also represent a resource for future research on H. annosum-conifer pathosystems.

National Category
Agricultural Sciences
Identifiers
urn:nbn:se:uu:diva-216593 (URN)10.1016/j.plantsci.2004.08.010 (DOI)000226558800010 ()
Available from: 2014-01-23 Created: 2014-01-23 Last updated: 2017-12-06Bibliographically approved
Asiegbu, F., Choi, W., Li, G., Nahalkova, J. & Dean, R. (2003). Isolation of a novel antimicrobal peptide gene (Sp-AMP) homologue from Pinus sylvestris (Scots pine) following infection with the root rot fungus Heterobasidion annosum. FEMS Microbiology Letters, 228(1), 27-31
Open this publication in new window or tab >>Isolation of a novel antimicrobal peptide gene (Sp-AMP) homologue from Pinus sylvestris (Scots pine) following infection with the root rot fungus Heterobasidion annosum
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2003 (English)In: FEMS Microbiology Letters, ISSN 0378-1097, E-ISSN 1574-6968, Vol. 228, no 1, p. 27-31Article in journal (Refereed) Published
Abstract [en]

A new family of antimicrobial peptide homologues termed Sp-Amp has been discovered in Pinus sylvestris (Scots pine). This is the first report of such proteins to be characterized in a conifer species. Sp-AMP1 was identified in a substructured cDNA library of root tissue infected with the root rot fungus Heterobasidion annosum and encodes a mature peptide of 79 amino acid residues. Three additional members of the Sp-AMP family (Sp-AMPs 2–4) encode cysteine-rich proteins of 105 amino acids, each containing an N-terminal region with a probable cleavage signal sequence. Northern analysis confirmed that Sp-AMP expression is elevated in Scots pine roots upon infection with H. annosum. These peptides share 64% amino acid identity with a mature protein from Macadamia integrifolia (MiAMP1), which allowed us to build a homology model for preliminary analysis. Southern analyses further confirmed that several copies of the gene are present in the Scots pine genome. The potential significance of Sp-AMP in the H. annosum–conifer pathosystem is discussed.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-47430 (URN)10.1016/S0378-1097(03)00697-9 (DOI)
Available from: 2008-10-17 Created: 2008-10-17 Last updated: 2017-12-05Bibliographically approved
Asiegbu, F. O., Choi, W. B., Li, G. S., Nahalkova, J. & Dean, R. A. (2003). Isolation of a novel antimicrobial peptide gene (Sp-AMP) homologue from Pinus sylvestris (Scots pine) following infection with the root root fungus Heterobasidion annosum. FEMS Microbiology Letters, 228(1), 27-31
Open this publication in new window or tab >>Isolation of a novel antimicrobial peptide gene (Sp-AMP) homologue from Pinus sylvestris (Scots pine) following infection with the root root fungus Heterobasidion annosum
Show others...
2003 (English)In: FEMS Microbiology Letters, ISSN 0378-1097, E-ISSN 1574-6968, Vol. 228, no 1, p. 27-31Article in journal (Refereed) Published
Abstract [en]

A new family of antimicrobial peptide homologues termed Sp-Amp has been discovered in Pinus sylvestris (Scots pine). This is the first report of such proteins to be characterized in a conifer species. Sp-AMP1 was identified in a substructured cDNA library of root tissue infected with the root rot fungus Heterobasidion annosum and encodes a mature peptide of 79 amino acid residues. Three additional members of the Sp-AMP family (Sp-AMPs 2-4) encode cysteine-rich proteins of 105 amino acids, each containing an N-terminal region with a probable cleavage signal sequence. Northern analysis confirmed that Sp-AMP expression is elevated in Scots pine roots upon infection with H. annosum. These peptides share 64% amino acid identity with a mature protein from Macadamia integrifolia (MiAMP1), which allowed us to build a homology model for preliminary analysis. Southern analyses further confirmed that several copies of the gene are present in the Scots pine genome. The potential significance of Sp-AMP in the H. annosum-conifer pathosystem is discussed.

National Category
Agricultural Sciences
Identifiers
urn:nbn:se:uu:diva-216595 (URN)10.1016/S0378-1097(03)00697-9 (DOI)000186586900004 ()
Available from: 2014-01-23 Created: 2014-01-23 Last updated: 2017-12-06Bibliographically approved
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