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Hellman, Ulf
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Publications (10 of 78) Show all publications
Lampropoulou, E., Logoviti, I., Koutsioumpa, M., Hatziapostolou, M., Polytarchou, C., Skandalis, S. S., . . . Papadimitriou, E. (2018). Cyclin-dependent kinase 5 mediates pleiotrophin-induced endothelial cell migration. Scientific Reports, 8, Article ID 5893.
Open this publication in new window or tab >>Cyclin-dependent kinase 5 mediates pleiotrophin-induced endothelial cell migration
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2018 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 5893Article in journal (Refereed) Published
Abstract [en]

Pleiotrophin (PTN) stimulates endothelial cell migration through binding to receptor protein tyrosine phosphatase beta/zeta (RPTP beta/zeta) and alpha(nu)beta(3) integrin. Screening for proteins that interact with RPTP beta/zeta and potentially regulate PTN signaling, through mass spectrometry analysis, identified cyclindependent kinase 5 (CDK5) activator p35 among the proteins displaying high sequence coverage. Interaction of p35 with the serine/threonine kinase CDK5 leads to CDK5 activation, known to be implicated in cell migration. Protein immunoprecipitation and proximity ligation assays verified p35-RPTP beta/zeta interaction and revealed the molecular association of CDK5 and RPTP beta/zeta. In endothelial cells, PTN activates CDK5 in an RPTP beta/zeta- and phosphoinositide 3-kinase (PI3K)-dependent manner. On the other hand, c-Src, alpha(nu)beta(3) and ERK1/2 do not mediate the PTN-induced CDK5 activation. Pharmacological and genetic inhibition of CDK5 abolished PTN-induced endothelial cell migration, suggesting that CDK5 mediates PTN stimulatory effect. A new pyrrolo[2,3-alpha] carbazole derivative previously identified as a CDK1 inhibitor, was found to suppress CDK5 activity and eliminate PTN stimulatory effect on cell migration, warranting its further evaluation as a new CDK5 inhibitor. Collectively, our data reveal that CDK5 is activated by PTN, in an RPTP beta/zeta-dependent manner, regulates PTN-induced cell migration and is an attractive target for the inhibition of PTN pro-angiogenic properties.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-352477 (URN)10.1038/s41598-018-24326-x (DOI)000429785900033 ()29651006 (PubMedID)
Available from: 2018-11-06 Created: 2018-11-06 Last updated: 2022-09-15Bibliographically approved
Gemoll, T., Masche, A., Roblick, U. J., Bader, F., Unger, A., Becker, S., . . . Habermann, J. (2018). Protein expression of CSTF2T and ACTB discern sporadic from FAP-associated colon carcinomas at various stages of carcinogenesis. Oncology Research and Treatment, 41, 173-173
Open this publication in new window or tab >>Protein expression of CSTF2T and ACTB discern sporadic from FAP-associated colon carcinomas at various stages of carcinogenesis
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2018 (English)In: Oncology Research and Treatment, ISSN 2296-5270, E-ISSN 2296-5262, Vol. 41, p. 173-173Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
KARGER, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-494756 (URN)000424914300476 ()
Available from: 2023-01-20 Created: 2023-01-20 Last updated: 2023-01-20Bibliographically approved
Chen, Z. X., Wallis, K., Fell, S. M., Sobrado, V. R., Hemmer, M. C., Ramsköld, D., . . . Schlisio, S. (2014). RNA helicase A is a downstream mediator of KIF1Bβ tumor-suppressor function in neuroblastoma. Cancer Discovery, 4(4), 434-451
Open this publication in new window or tab >>RNA helicase A is a downstream mediator of KIF1Bβ tumor-suppressor function in neuroblastoma
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2014 (English)In: Cancer Discovery, ISSN 2159-8274, E-ISSN 2159-8290, Vol. 4, no 4, p. 434-451Article in journal (Refereed) Published
Abstract [en]

UNLABELLED: Inherited KIF1B loss-of-function mutations in neuroblastomas and pheochromocytomas implicate the kinesin KIF1B as a 1p36.2 tumor suppressor. However, the mechanism of tumor suppression is unknown. We found that KIF1B isoform β (KIF1Bβ) interacts with RNA helicase A (DHX9), causing nuclear accumulation of DHX9, followed by subsequent induction of the proapoptotic XIAP-associated factor 1 (XAF1) and, consequently, apoptosis. Pheochromocytoma and neuroblastoma arise from neural crest progenitors that compete for growth factors such as nerve growth factor (NGF) during development. KIF1Bβ is required for developmental apoptosis induced by competition for NGF. We show that DHX9 is induced by and required for apoptosis stimulated by NGF deprivation. Moreover, neuroblastomas with chromosomal deletion of 1p36 exhibit loss of KIF1Bβ expression and impaired DHX9 nuclear localization, implicating the loss of DHX9 nuclear activity in neuroblastoma pathogenesis.

SIGNIFICANCE: KIF1Bβ has neuroblastoma tumor-suppressor properties and promotes and requires nuclear-localized DHX9 for its apoptotic function by activating XAF1 expression. Loss of KIF1Bβ alters subcellular localization of DHX9 and diminishes NGF dependence of sympathetic neurons, leading to reduced culling of neural progenitors, and, therefore, might predispose to tumor formation.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-231916 (URN)10.1158/2159-8290.CD-13-0362 (DOI)000334347300024 ()24469107 (PubMedID)
Funder
Swedish Childhood Cancer FoundationThe Swedish Brain FoundationSwedish Research CouncilSwedish Cancer SocietyÅke Wiberg Foundation
Available from: 2014-09-11 Created: 2014-09-11 Last updated: 2017-12-05Bibliographically approved
Gemoll, T., Habermann, J. K., Lahmann, J., Szymczak, S., Lundgren, C., Bündgen, N. K., . . . Jörnvall, H. (2012). Protein profiling of genomic instability in endometrial cancer. Cellular and Molecular Life Sciences (CMLS), 69(2), 325-333
Open this publication in new window or tab >>Protein profiling of genomic instability in endometrial cancer
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2012 (English)In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 69, no 2, p. 325-333Article in journal (Refereed) Published
Abstract [en]

DNA aneuploidy has been identified as a prognostic factor in the majority of epithelial malignancies. We aimed at identifying ploidy-associated protein expression in endometrial cancer of different prognostic subgroups. Comparison of gel electrophoresis-based protein expression patterns between normal endometrium (n = 5), diploid (n = 7), and aneuploid (n = 7) endometrial carcinoma detected 121 ploidy-associated protein forms, 42 differentially expressed between normal endometrium and diploid endometrioid carcinomas, 37 between diploid and aneuploid endometrioid carcinomas, and 41 between diploid endometrioid and aneuploid uterine papillary serous cancer. Proteins were identified by mass spectrometry and evaluated by Ingenuity Pathway Analysis. Targets were confirmed by liquid chromatography/mass spectrometry. Mass spectrometry identified 41 distinct polypeptides and pathway analysis resulted in high-ranked networks with vimentin and Nf-kappa B as central nodes. These results identify ploidy-associated protein expression differences that overrule histopathology-associated expression differences and emphasize particular protein networks in genomic stability of endometrial cancer.

Place, publisher, year, edition, pages
Springer, 2012
Keywords
Aneuploidy, Endometrial carcinoma, Genomic instability, Mass spectrometry, Pathway analysis, Two-dimensional gel electrophoresis
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-168100 (URN)10.1007/s00018-011-0752-0 (DOI)000298653500011 ()
Available from: 2012-02-07 Created: 2012-02-06 Last updated: 2020-08-09Bibliographically approved
Feliziani, C., Merino, M. C., Rivero, M. R., Hellman, U., Pistoresi-Palencia, M. C. & Rópolo, A. S. (2011). Immunodominant proteins α-1 giardin and β-giardin are expressed in both assemblages A and B of Giardia lamblia. BMC Microbiology, 11, 233
Open this publication in new window or tab >>Immunodominant proteins α-1 giardin and β-giardin are expressed in both assemblages A and B of Giardia lamblia
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2011 (English)In: BMC Microbiology, E-ISSN 1471-2180, Vol. 11, p. 233-Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: To date, eight assemblages of Giardia lamblia have been described, but only assemblages A and B are known to infect humans. Despite the fact that the genomic, biological, and clinical differences found between these two assemblages has raised the possibility that they may be considered different species, there is relatively limited information on their phenotypic differences. In the present study, we developed monoclonal antibodies against alpha-1 and beta giardin, two immunodominant proteins produced during G. lamblia infection, and studied their expression and localization in WB (assemblage A) and GS trophozoites (assemblage B).

RESULTS: The polyclonal antibodies generated against WB trophozoites, particularly those recognizing intracellular proteins as well as the proteins present at the plasma membrane (variable-specific surface proteins), showed cross-reactivity with intracellular proteins in GS trophozoites. The use of monoclonal antibodies against beta giardin indicated ventral disc localization, particularly at the periphery in WB trophozoites. Interestingly, although beta giardin was also restricted to the ventral disc in GS trophozoites, the pattern of localization clearly differed in this assemblage. On the other hand, monoclonal antibodies against alpha-1 giardin showed plasma membrane localization in both assemblages with the bare area of GS trophozoites also being distinguished. Moreover, the same localization at the plasma membrane was observed in Portland-1 (Assemblage A) and in P15 (Assemblage E) trophozoites.

CONCLUSIONS: We found differences in localization of the beta giardin protein between assemblages A and B, but the same pattern of localization of alpha-1 giardin in strains from Assemblages A, B and E. These findings reinforce the need for more studies based on phenotypic characteristics in order to disclose how far one assemblage is from the other.

Keywords
mathematical model, Smad, TGF-beta, ultrasensitivity
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-161166 (URN)10.1186/1471-2180-11-233 (DOI)000296636600001 ()22011206 (PubMedID)
Available from: 2011-11-08 Created: 2011-11-08 Last updated: 2024-01-17Bibliographically approved
Bhaskaran, N., Lin, K. W., Gautier, A., Woksepp, H., Hellman, U. & Souchelnytskyi, S. (2009). Comparative proteome profiling of MCF10A and 184A1 human breast epithelial cells emphasized involvement of CDK4 and cyclin D3 in cell proliferation. Proteomics Clinical Applications, 3(1), 68-77
Open this publication in new window or tab >>Comparative proteome profiling of MCF10A and 184A1 human breast epithelial cells emphasized involvement of CDK4 and cyclin D3 in cell proliferation
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2009 (English)In: Proteomics Clinical Applications, ISSN 1862-8354, Vol. 3, no 1, p. 68-77Article in journal (Refereed) Published
Abstract [en]

Acquiring high proliferation rate is crucial for carcinogenic transformation of cells. We reporthere proteome profiling of human breast epithelial cells with low (184A1) and high (MCF10A)proliferation rates.We identified 183 proteins in 184A1 and 318 proteins in MCF10A cells. Thesedatasets provide the most comprehensive proteome annotations of 184A1 and MCF10A cells.Proteins were taken for identification from 2-D gels in a systematic and unbiased way. Functionalclustering of the identified proteins showed similarities in distribution of proteins to the samefunctional domains, indicating similarities in proteomes of 184A1 and MCF10A cells. Amongobserved differences in protein expression, we validated correlation of expression of endogenouscyclin-dependent kinase 4 (CDK4), cyclin D3, cdc25B, and p38g with cell proliferation. Furthermore,down-regulation of CDK4 and cyclin D3 with specific siRNA inhibited cell proliferation,which emphasized the role of CDK4 and cyclin D3 in enhancement of cell proliferation rate ofhuman breast epithelial cells.

Keywords
Breast epithelial cells, CDK4, Cyclin D3, Proliferation, Proteome profiling
National Category
Cancer and Oncology Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-106888 (URN)10.1002/prca.200800045 (DOI)000262893600008 ()
Available from: 2009-07-09 Created: 2009-07-09 Last updated: 2010-12-14Bibliographically approved
Bilyy, R., Kit, Y., Hellman, U. & Stoika, R. (2008). AMID: new insights on its intracellular localization and expression at apoptosis. Apoptosis (London), 13(5), 729-732
Open this publication in new window or tab >>AMID: new insights on its intracellular localization and expression at apoptosis
2008 (English)In: Apoptosis (London), ISSN 1360-8185, E-ISSN 1573-675X, Vol. 13, no 5, p. 729-732Article in journal (Refereed) Published
Abstract [en]

AMID (apoptosis-inducing factor (AIF)-like mitochondrion-associated inducer of death) is a poorly studied member of the AIF family; despite the given name AMID, predicting its association with mitochondria, its real cellular localization, as well as its role and changes during apoptosis are currently unclear. By means of MALDI-TOF mass spectrometry, we have identified as AMID (accession number AAH38129, sequence coverage 31%) the protein isolated by Pisum sativum lectin-affinity chromatography from the plasma membrane fraction of apoptotic murine leukemia L1210 cells, lacking in the intact cells. The obtained results suggest its possible glycosylation that was further suggested by finding N-glycosylation sequon in the signal peptide of AMID protein (in silica), and by predicting transmembrane localization of its N-terminal part. Using monoclonal antibodies to AMID, we demonstrated an increased expression of AMID in human leukemia Jurkat T-cells after apoptosis induction. Immunocytochemical study suggested its association to the plasma membrane.

Keywords
AMID, AIF, Apoptosis, Plasma membrane, Glycosylation, Lectin, MALDI-TOF MS
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-16086 (URN)10.1007/s10495-008-0198-5 (DOI)000255030400012 ()18368494 (PubMedID)
Available from: 2008-04-18 Created: 2008-04-18 Last updated: 2017-12-08Bibliographically approved
Cabrera, G., Cabrejos, M. E., Morassutti, A. L., Cabezón, C., Orellana, J., Hellman, U., . . . Galanti, N. (2008). DNA damage, RAD9 and fertility/infertility of Echinococcus granulosus hydatid cysts. Journal of Cellular Physiology, 216(2), 498-506
Open this publication in new window or tab >>DNA damage, RAD9 and fertility/infertility of Echinococcus granulosus hydatid cysts
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2008 (English)In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 216, no 2, p. 498-506Article in journal (Refereed) Published
Abstract [en]

Hydatidosis, caused by the larval stage of the platyhelminth parasite Echinococcus granulosus, affects human and animal health. Hydatid fertile cysts are formed in intermediate hosts (human and herbivores) producing protoscoleces, the infective form to canines, at their germinal layers. Infertile cysts are also formed, but they are unable to produce protoscoleces. The molecular mechanisms involved in hydatid cysts fertility/infertility are unknown. Nevertheless, previous work from our laboratory has suggested that apoptosis is involved in hydatid cyst infertility and death. On the other hand, fertile hydatid cysts can resist oxidative damage due to reactive oxygen and nitrogen species. On these foundations, we have postulated that when oxidative damage of DNA in the germinal layers exceeds the capability of DNA repair mechanisms, apoptosis is triggered and hydatid cysts infertility occurs. We describe a much higher percentage of nuclei with oxidative DNA damage in dead protoscoleces and in the germinal layer of infertile cysts than in fertile cysts, suggesting that DNA repair mechanisms are active in fertile cysts. rad9, a conserved gene, plays a key role in cell cycle checkpoint modulation and DNA repair. We found that RAD9 of E. granulosus (EgRAD9) is expressed at the mRNA and protein levels. As it was found in other eukaryotes, EgRAD9 is hyperphosphorylated in response to DNA damage. Our results suggest that molecules involved in DNA repair in the germinal layer of fertile hydatid cysts and in protoscoleces, such as EgRAD9, may allow preserving the fertility of hydatid cysts in the presence of ROS and RNS.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-17588 (URN)10.1002/jcp.21418 (DOI)000257352500027 ()18348165 (PubMedID)
Available from: 2008-07-10 Created: 2008-07-10 Last updated: 2017-12-08Bibliographically approved
Bardales, J. R., Hellman, U. & Villamarín, J. A. (2008). Identification of multiple isoforms of the cAMP-dependent protein kinase catalytic subunit in the bivalve mollusc Mytilus galloprovincialis. The FEBS Journal, 275(18), 4479-4489
Open this publication in new window or tab >>Identification of multiple isoforms of the cAMP-dependent protein kinase catalytic subunit in the bivalve mollusc Mytilus galloprovincialis
2008 (English)In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 275, no 18, p. 4479-4489Article in journal (Refereed) Published
Abstract [en]

Several isoforms of the cAMP-dependent protein kinase catalytic subunit (C-subunit) were separated from the posterior adductor muscle and the mantle tissues of the sea mussel Mytilus galloprovincialis by cation exchange chromatography, and identified by: (a) protein kinase activity; (b) antibody recognition; and (c) peptide mass fingerprinting. Some of the isozymes seemed to be tissue-specific, and all them were phosphorylated at serine and threonine residues and showed slight but significant differences in their apparent molecular mass values, which ranged from 41.3 to 44.5 kDa. The results from the MS analysis suggest that at least some of the mussel C-subunit isoforms arise as a result of alternative splicing events. Furthermore, several peptide sequences from mussel C-subunits, determined by de novo sequencing, showed a high degree of homology with the mammalian Calpha-isoform, and contained some structural motifs that are essential for catalytic function. On the other hand, no significant differences were observed in the kinetic parameters of C-subunit isoforms, determined by using synthetic peptides as substrate and inhibitor. However, the C-subunit isoforms separated from the mantle tissue differed in their ability to phosphorylate in vitro some proteins present in a mantle extract.

Keywords
cAMP-dependent protein kinase, catalytic subunit, C-subunit isoforms, MALDI-TOF⁄ TOF MS, Mytilus
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-85619 (URN)10.1111/j.1742-4658.2008.06591.x (DOI)000258729100006 ()18671732 (PubMedID)
Available from: 2008-10-23 Created: 2008-10-23 Last updated: 2017-12-14Bibliographically approved
Conrotto, P. & Hellman, U. (2008). Lys Tag: an easy and robust chemical modification for improved de novo sequencing with a matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometer. Rapid Communications in Mass Spectrometry, 22(12), 1823-33
Open this publication in new window or tab >>Lys Tag: an easy and robust chemical modification for improved de novo sequencing with a matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometer
2008 (English)In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 22, no 12, p. 1823-33Article in journal (Refereed) Published
Abstract [en]

Mass spectrometry using a matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) instrument is a widespread technique for various types of proteomic analysis. Along with an expanding interest in proteomics, there is a strong requirement for the identification of proteins with high confidence from biological samples. Peptide modification by a wide variety of post-translational modifications (PTMs), the existence of different protein isoforms and the presence of uncharacterized genomes of many species, make protein identification through peptide mass fingerprinting (PMF) often unachievable. Peptide de novo sequencing has been proven to be a useful approach to overcome these variables, and efficient derivatization processes are important tools to achieve this goal. In the present work we describe the methodology and experimental applications of a fast, efficient and cheap lysine derivatization. This chemical modification improves the signals from lysine-terminated peptides and can be efficiently used as a lysine-blocking agent in combination with other derivatization techniques. Most importantly, upon peptide fragmentation it generates a neat series of predominantly y-ions, allowing the determination of unambiguous amino acid sequences. Moreover, this chemical compound was used with target-eluted samples, enabling a second, alternative analysis of the same sample in the MALDI mass spectrometer.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-17572 (URN)10.1002/rcm.3555 (DOI)000256985100008 ()18470875 (PubMedID)
Available from: 2008-07-10 Created: 2008-07-10 Last updated: 2017-12-08Bibliographically approved
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