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Publications (10 of 11) Show all publications
Dahl-Halvarsson, M., Olive, M., Pokrzywa, M., Ejeskär, K., Palmer, R. H., Uv, A. E. & Tajsharghi, H. (2018). Drosophila model of myosin myopathy rescued by overexpression of a TRIM-protein family member. Proceedings of the National Academy of Sciences of the United States of America, 115(28), E6566-E6575
Open this publication in new window or tab >>Drosophila model of myosin myopathy rescued by overexpression of a TRIM-protein family member
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2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 28, p. E6566-E6575Article in journal (Refereed) Published
Abstract [en]

Myosin is a molecular motor indispensable for body movement and heart contractility. Apart from pure cardiomyopathy, mutations in MYH7 encoding slow/β-cardiac myosin heavy chain also cause skeletal muscle disease with or without cardiac involvement. Mutations within the α-helical rod domain of MYH7are mainly associated with Laing distal myopathy. To investigate the mechanisms underlying the pathology of the recurrent causative MYH7 mutation (K1729del), we have developed a Drosophila melanogaster model of Laing distal myopathy by genomic engineering of the Drosophila Mhc locus. Homozygous MhcK1728del animals die during larval/pupal stages, and both homozygous and heterozygous larvae display reduced muscle function. Flies expressing only MhcK1728del in indirect flight and jump muscles, and heterozygous MhcK1728del animals, were flightless, with reduced movement and decreased lifespan. Sarcomeres of MhcK1728del mutant indirect flight muscles and larval body wall muscles were disrupted with clearly disorganized muscle filaments. Homozygous MhcK1728del larvae also demonstrated structural and functional impairments in heart muscle, which were not observed in heterozygous animals, indicating a dose-dependent effect of the mutated allele. The impaired jump and flight ability and the myopathy of indirect flight and leg muscles associated with MhcK1728del were fully suppressed by expression of Abba/Thin, an E3-ligase that is essential for maintaining sarcomere integrity. This model of Laing distal myopathy in Drosophila recapitulates certain morphological phenotypic features seen in Laing distal myopathy patients with the recurrent K1729del mutation. Our observations that Abba/Thin modulates these phenotypes suggest that manipulation of Abba/Thin activity levels may be beneficial in Laing distal myopathy.

National Category
Genetics Neurology
Research subject
Biomedical Genetics
Identifiers
urn:nbn:se:his:diva-15878 (URN)10.1073/pnas.1800727115 (DOI)000438050900023 ()29946036 (PubMedID)2-s2.0-85049855441 (Scopus ID)
Available from: 2018-06-29 Created: 2018-06-29 Last updated: 2018-08-30Bibliographically approved
Chaudhari, A., Ejeskär, K., Wettergren, Y., Kahn, R. & Rotter Sopasakis, V. (2017). Hepatic deletion of p110α and p85α results in insulin resistance despite sustained IRS1-associated phosphatidylinositol kinase activity. F1000 Research, 6, Article ID 1600.
Open this publication in new window or tab >>Hepatic deletion of p110α and p85α results in insulin resistance despite sustained IRS1-associated phosphatidylinositol kinase activity
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2017 (English)In: F1000 Research, E-ISSN 2046-1402, Vol. 6, article id 1600Article in journal (Refereed) Published
Abstract [en]

Background: Class IA phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is an integral mediator of insulin signaling. The p110 catalytic and p85 regulatory subunits of PI3K are the products of separate genes, and while they come together to make the active heterodimer, they have opposing roles in insulin signaling and action. Deletion of hepatic p110α results in an impaired insulin signal and severe insulin resistance, whereas deletion of hepatic p85α results in improved insulin sensitivity due to sustained levels of phosphatidylinositol (3,4,5)-trisphosphate. Here, we created mice with combined hepatic deletion of p110α and p85α (L-DKO) to study the impact on insulin signaling and whole body glucose homeostasis.Methods: Six-week old male flox control and L-DKO mice were studied over a period of 18 weeks, during which weight and glucose levels were monitored, and glucose tolerance tests, insulin tolerance test and pyruvate tolerance test were performed. Fasting insulin, insulin signaling mediators, PI3K activity and insulin receptor substrate (IRS)1-associated phosphatidylinositol kinase activity were examined at 10 weeks. Liver, muscle and white adipose tissue weight was recorded at 10 weeks and 25 weeks.Results: The L-DKO mice showed a blunted insulin signal downstream of PI3K, developed markedly impaired glucose tolerance, hyperinsulinemia and had decreased liver and adipose tissue weights. Surprisingly, however, these mice displayed normal hepatic glucose production, normal insulin tolerance, and intact IRS1-associated phosphatidylinositol kinase activity without compensatory upregulated signaling of other classes of PI3K.Conclusions: The data demonstrate an unexpectedly overall mild metabolic phenotype of the L-DKO mice, suggesting that lipid kinases other than PI3Ks might partially compensate for the loss of p110α/p85α by signaling through other nodes than Akt/Protein Kinase B.

Keywords
phosphatidylinositol-4, 5-bisphosphate 3-kinase, p110, p85, insulin receptor substrate, insulin resistance, glucose intolerance
National Category
Medical Genetics Cell and Molecular Biology Cancer and Oncology Endocrinology and Diabetes
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-16079 (URN)10.12688/f1000research.12418.2 (DOI)29983910 (PubMedID)2-s2.0-85049310506 (Scopus ID)
Funder
Swedish Research CouncilMagnus Bergvall FoundationNIH (National Institute of Health), DK055545
Available from: 2018-08-24 Created: 2018-08-24 Last updated: 2018-10-23Bibliographically approved
Visuttijai, K., Pettersson, J., Mehrbani Azar, Y., van den Bout, I., Örndal, C., Marcickiewicz, J., . . . Behboudi, A. (2016). Lowered Expression of Tumor Suppressor Candidate MYO1CStimulates Cell Proliferation, Suppresses Cell Adhesion and Activates AKT. PLoS ONE, 11(10), Article ID e0164063.
Open this publication in new window or tab >>Lowered Expression of Tumor Suppressor Candidate MYO1CStimulates Cell Proliferation, Suppresses Cell Adhesion and Activates AKT
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0164063Article in journal (Refereed) Published
Abstract [en]

Myosin-1C (MYO1C) is a tumor suppressor candidate located in a region of recurrent losses distal to TP53. Myo1c can tightly and specifically bind to PIP2, the substrate of Phosphoinositide 3-kinase (PI3K), and to Rictor, suggesting a role for MYO1C in the PI3K pathway. This study was designed to examine MYO1C expression status in a panel of well-stratified endometrial carcinomas as well as to assess the biological significance of MYO1C as a tumor suppressor in vitro. We found a significant correlation between the tumor stage and lowered expression of MYO1C in endometrial carcinoma samples. In cell transfection experiments, we found a negative correlation between MYO1C expression and cell proliferation, and MYO1C silencing resulted in diminished cell migration and adhesion. Cells expressing excess of MYO1C had low basal level of phosphorylated protein kinase B (PKB, a.k.a. AKT) and cells with knocked down MYO1C expression showed a quicker phosphorylated AKT (pAKT) response in reaction to serum stimulation. Taken together the present study gives further evidence for tumor suppressor activity of MYO1C and suggests MYO1C mediates its tumor suppressor function through inhibition of PI3K pathway and its involvement in loss of contact inhibition.

Place, publisher, year, edition, pages
Public Library of Science, 2016
Keywords
MYO1C, myosin-1c, tumor suppressor, AKT signaling
National Category
Other Medical Sciences
Research subject
Medical sciences; Bioinformatics
Identifiers
urn:nbn:se:his:diva-13020 (URN)10.1371/journal.pone.0164063 (DOI)000385698100017 ()27716847 (PubMedID)2-s2.0-84991449467 (Scopus ID)
Projects
Cellular, Molecular and Functional Characterization of the Tumor Suppressor Candidate MYO1C
Available from: 2016-10-11 Created: 2016-10-11 Last updated: 2019-11-18
Jurcevic, S., Klinga-Levan, K., Olsson, B. & Ejeskär, K. (2016). Verification of microRNA expression in human endometrial adenocarcinoma. BMC Cancer, 16(1), Article ID 261.
Open this publication in new window or tab >>Verification of microRNA expression in human endometrial adenocarcinoma
2016 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 16, no 1, article id 261Article in journal (Refereed) Published
Place, publisher, year, edition, pages
BioMed Central, 2016
National Category
Cancer and Oncology
Research subject
Biomedical Genetics; Bioinformatics; Infection Biology
Identifiers
urn:nbn:se:his:diva-10890 (URN)10.1186/s12885-016-2296-z (DOI)000373329900001 ()27039384 (PubMedID)2-s2.0-84962003924 (Scopus ID)
Available from: 2015-05-05 Created: 2015-05-05 Last updated: 2019-01-16Bibliographically approved
Chaudhari, A., Krumlinde, D., Lundqvist, A., Akyurek, L. M., Bandaru, S., Skalen, K., . . . Sopasakis, V. R. (2015). p110 alpha Hot Spot Mutations E545K and H1047R Exert Metabolic Reprogramming Independently of p110 alpha Kinase Activity. Molecular and Cellular Biology, 35(19), 3258-3273
Open this publication in new window or tab >>p110 alpha Hot Spot Mutations E545K and H1047R Exert Metabolic Reprogramming Independently of p110 alpha Kinase Activity
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2015 (English)In: Molecular and Cellular Biology, ISSN 0270-7306, Vol. 35, no 19, p. 3258-3273Article in journal (Refereed) Published
Abstract [en]

The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit p110α is the most frequently mutated kinase in human cancer, and the hot spot mutations E542K, E545K, and H1047R are the most common mutations in p110α. Very little is known about the metabolic consequences of the hot spot mutations of p110α in vivo. In this study, we used adenoviral gene transfer in mice to investigate the effects of the E545K and H1047R mutations on hepatic and whole-body glucose metabolism. We show that hepatic expression of these hot spot mutations results in rapid hepatic steatosis, paradoxically accompanied by increased glucose tolerance, and marked glycogen accumulation. In contrast, wild-type p110α expression does not lead to hepatic accumulation of lipids or glycogen despite similar degrees of upregulated glycolysis and expression of lipogenic genes. The reprogrammed metabolism of the E545K and H1047R p110α mutants was surprisingly not dependent on altered p110α lipid kinase activity.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Bioinformatics and Systems Biology Biochemistry and Molecular Biology
Research subject
Biomedical Genetics
Identifiers
urn:nbn:se:his:diva-13592 (URN)10.1128/MCB.00471-15 (DOI)000365391300001 ()26169833 (PubMedID)2-s2.0-84941052983 (Scopus ID)
Available from: 2017-05-23 Created: 2017-05-23 Last updated: 2019-02-19Bibliographically approved
Chaudhari, A., Krumlinde, D., Lundqvist, A., Akyürek, L. M., Bandaru, S., Skålén, K., . . . Rotter Sopasakis, V. (2015). p110α hot spot mutations E545K and H1047R exert metabolic reprogramming independently of p110α kinase activity. Molecular and Cellular Biology, 35(19), 3258-3273
Open this publication in new window or tab >>p110α hot spot mutations E545K and H1047R exert metabolic reprogramming independently of p110α kinase activity
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2015 (English)In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 35, no 19, p. 3258-3273Article in journal (Refereed) Published
Abstract [en]

The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit p110α is the most frequently mutated kinase in human cancer, and the hot spot mutations E542K, E545K, and H1047R are the most common mutations in p110α. Very little is known about the metabolic consequences of the hot spot mutations of p110α in vivo. In this study, we used adenoviral gene transfer in mice to investigate the effects of the E545K and H1047R mutations on hepatic and whole-body glucose metabolism. We show that hepatic expression of these hot spot mutations results in rapid hepatic steatosis, paradoxically accompanied by increased glucose tolerance, and marked glycogen accumulation. In contrast, wild-type p110α expression does not lead to hepatic accumulation of lipids or glycogen despite similar degrees of upregulated glycolysis and expression of lipogenic genes. The reprogrammed metabolism of the E545K and H1047R p110α mutants was surprisingly not dependent on altered p110α lipid kinase activity.

Place, publisher, year, edition, pages
American Society for Microbiology, 2015
National Category
Medical Genetics Cell and Molecular Biology
Research subject
Medical sciences
Identifiers
urn:nbn:se:his:diva-11449 (URN)10.1128/MCB.00471-15 (DOI)26169833 (PubMedID)2-s2.0-84941052983 (Scopus ID)
Funder
Swedish Childhood Cancer FoundationSwedish Research CouncilKnowledge Foundation
Available from: 2015-08-28 Created: 2015-08-28 Last updated: 2018-01-11Bibliographically approved
Ejeskär, K., Vickes, O., Kuchipudi, A., Wettergren, Y., Uv, A. & Rotter Sopasakis, V. (2015). The unique non-catalytic C-terminus of p37delta-PI3K adds proliferative properties in vitro and in vivo. PLoS ONE, 10(5), Article ID e0127497.
Open this publication in new window or tab >>The unique non-catalytic C-terminus of p37delta-PI3K adds proliferative properties in vitro and in vivo
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0127497Article in journal (Refereed) Published
Abstract [en]

The PI3K/Akt pathway is central for numerous cellular functions and is frequently deregulated in human cancers. The catalytic subunits of PI3K, p110, are thought to have a potential oncogenic function, and the regulatory subunit p85 exerts tumor suppressor properties. The fruit fly, Drosophila melanogaster, is a highly suitable system to investigate PI3K signaling, expressing one catalytic, Dp110, and one regulatory subunit, Dp60, and both show strong homology with the human PI3K proteins p110 and p85. We recently showed that p37δ, an alternatively spliced product of human PI3K p110δ, displayed strong proliferation-promoting properties despite lacking the catalytic domain completely. Here we functionally evaluate the different domains of human p37δ in Drosophila. The N-terminal region of Dp110 alone promotes cell proliferation, and we show that the unique C-terminal region of human p37δ further enhances these proliferative properties, both when expressed in Drosophila, and in human HEK-293 cells. Surprisingly, although the N-terminal region of Dp110 and the C-terminal region of p37δ both display proliferative effects, over-expression of full length Dp110 or the N-terminal part of Dp110 decreases survival in Drosophila, whereas the unique C-terminal region of p37δ prevents this effect. Furthermore, we found that the N-terminal region of the catalytic subunit of PI3K p110, including only the Dp60 (p85)-binding domain and a minor part of the Ras binding domain, rescues phenotypes with severely impaired development caused by Dp60 over-expression in Drosophila, possibly by regulating the levels of Dp60, and also by increasing the levels of phosphorylated Akt. Our results indicate a novel kinase-independent function of the PI3K catalytic subunit.

Place, publisher, year, edition, pages
PLOS, 2015
National Category
Medical Genetics Cell and Molecular Biology
Research subject
Medical sciences
Identifiers
urn:nbn:se:his:diva-11448 (URN)10.1371/journal.pone.0127497 (DOI)000355319400038 ()26024481 (PubMedID)2-s2.0-84932614925 (Scopus ID)
Funder
Swedish Childhood Cancer FoundationKnowledge FoundationSwedish Research Council
Available from: 2015-08-28 Created: 2015-08-28 Last updated: 2018-01-11Bibliographically approved
Fransson, S., Kogner, P., Martinsson, T. & Ejeskär, K. (2013). Aggressive neuroblastomas have high p110alpha but low p110delta and p55alpha/p50alpha protein levels compared to low stage neuroblastomas. Journal of Molecular Signaling, 8(1), Article ID 4.
Open this publication in new window or tab >>Aggressive neuroblastomas have high p110alpha but low p110delta and p55alpha/p50alpha protein levels compared to low stage neuroblastomas
2013 (English)In: Journal of Molecular Signaling, ISSN 1750-2187, E-ISSN 1750-2187, Vol. 8, no 1, article id 4Article in journal (Refereed) Published
Abstract [en]

Background: The phosphoinositide 3-kinase (PI3K)/Akt pathway is involved in neuroblastoma development where Akt/PKB activation is associated with poor prognosis. PI3K activity subsequently activates Akt/PKB, and as mutations of PI3K are rare in neuroblastoma and high levels of PI3K subunit p110delta is associated with favorable disease with low p-Akt/PKB, the levels of other PI3K subunits could be important for Akt activation.Methods: Protein levels of Type IA PI3K catalytic and regulatory subunits were investigated together with levels of phosphorylated Akt/PKB and the PI3K negative regulator PTEN in primary neuroblastoma tumors. Relation between clinical markers and protein levels were evaluated through t-tests. Results: We found high levels of p-Akt/PKB correlating to aggressive disease and p-Akt/PKB (T308) showed inverse correlation to PTEN levels. The regulatory isomers p55alpha/p50alpha showed higher levels in favorable neuroblastoma as compared with aggressive neuroblastoma. The PI3K-subunit p110alpha was found mainly in advanced tumors while p110delta showed higher levels in favorable neuroblastoma.Conclusions: Activation of the PI3K/Akt pathway is seen in neuroblastoma tumors, however the contribution of the different PI3K isoforms is unknown. Here we show that p110alpha is preferentially expressed in aggressive neuroblastomas, with high p-Akt/PKB and p110delta is mainly detected in favorable neuroblastomas, with low p-Akt/PKB. This is an important finding as PI3K-specific inhibitors are suggested for enrollment in treatment of neuroblastoma patients. © 2013 Fransson et al.; licensee BioMed Central Ltd.

Place, publisher, year, edition, pages
BioMed Central, 2013
Keywords
Akt, Neuroblastoma, Phosphoinositide 3-kinase, PI3K, Signaling
National Category
Natural Sciences
Research subject
Natural sciences
Identifiers
urn:nbn:se:his:diva-8430 (URN)10.1186/1750-2187-8-4 (DOI)23597230 (PubMedID)2-s2.0-84876198070 (Scopus ID)
Available from: 2013-08-19 Created: 2013-08-19 Last updated: 2017-12-06Bibliographically approved
Fransson, S. & Ejeskär, K. (2013). High level of p37δ-mRNA relative to p110δ-mRNA in neuroblastoma tumors correlates with poor patient survival. Medical Oncology, 30(4), Article ID 724.
Open this publication in new window or tab >>High level of p37δ-mRNA relative to p110δ-mRNA in neuroblastoma tumors correlates with poor patient survival
2013 (English)In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 30, no 4, article id 724Article in journal (Refereed) Published
Abstract [en]

Alterations in the PI3K/Akt pathway, a pathway that promotes proliferation and oncogenic transformation, are common in various cancers. In neuroblastoma, activation of Akt is correlated with aggressive disease although mutations in genes of this pathway are rare. Previous findings include a few mutations in PIK3CD, the gene encoding PI3K catalytic subunit delta, p110delta. We recently reported that an alternatively spliced form of p110delta, called p37delta, had cell proliferative properties and was over-expressed in ovarian and colorectal tumors. Here, we investigated p37delta in neuroblastoma primary tumors of different stages using qPCR (TaqMan) for gene expression analysis (46 samples) and Western blot for protein analysis (22 samples). Elevated levels of both p37delta-mRNA and p110delta-mRNA were detected in metastasizing neuroblastoma tumors compared to normal adrenal gland (P<0.05), and higher expression of p37delta-mRNA relative to p110delta-mRNA in neuroblastoma non-survivor patients compared to survivors (P<0.01). p37delta-Protein levels but not p110delta levels correlated with increased pAKT(T308) and pERK levels. The p37delta-mRNA levels did not correlate with the protein levels, indicating major regulation at the translational/protein level. Deregulation of signaling pathways is a hallmark of cancer development. Here, we show that p37delta, a kinase-dead isoform of the PI3K catalytic subunit p110delta, is over-expressed in neuroblastoma tumors, and that it correlates with the activation of both PI3K/Akt- and RAS-signaling pathways.

Place, publisher, year, edition, pages
Springer Science+Business Media B.V., 2013
Keywords
p110d, p37d, Neuroblastoma, PI3K
National Category
Natural Sciences
Research subject
Natural sciences
Identifiers
urn:nbn:se:his:diva-8596 (URN)10.1007/s12032-013-0724-3 (DOI)000327858800039 ()24026661 (PubMedID)2-s2.0-84883626316 (Scopus ID)
Note

Alternativ titel: High level of p37delta-mRNA relative to p110delta-mRNA in neuroblastoma tumors correlates with poor patient survival

Available from: 2013-10-30 Created: 2013-10-30 Last updated: 2017-12-06Bibliographically approved
Fransson, S., Abel, F., Kogner, P., Martinsson, T. & Ejeskär, K. (2013). Stage-dependent expression of PI3K/Akt‑pathway genes in neuroblastoma. International Journal of Oncology, 42(2), 609-616
Open this publication in new window or tab >>Stage-dependent expression of PI3K/Akt‑pathway genes in neuroblastoma
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2013 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 42, no 2, p. 609-616Article in journal (Refereed) Published
Abstract [en]

The phosphoinositide-3 kinase (PI3K) pathway plays a critical role in cancer cell growth and survival and has also been implicated in the development of the childhood cancer neuroblastoma. In neuroblastoma high mRNA expression of the PI3K catalytic isoform PIK3CD is associated to favorable disease. Yet, activation of Akt is associated with poor prognosis. Since the contribution of the numerous members of this pathway to neuroblastoma pathogenesis is mainly unknown, genes of the PI3K/Akt pathway were analyzed at the mRNA level through microarrays and quantitative real-time RT-PCR (TaqMan) and at the protein level using western blot analysis. Five genes showed lower mRNA expression in aggressive compared to more favorable neuroblastomas (PRKCZ, PRKCB1, EIF4EBP1, PIK3RI and PIK3CD) while the opposite was seen for PDGFRA. Clustering analysis shows that the expression levels of these six genes can predict aggressive disease. At the protein level, p110δ (encoded by PIK3CD) and p85α isomers (encoded by PIK3R1) were more highly expressed in favorable compared to aggressive neuroblastoma. Evaluation of the expression of these PI3K genes can predict aggressive disease, and indicates stage-dependent involvement of PI3K-pathway members in neuroblastoma.

Place, publisher, year, edition, pages
Spandidos Publications, 2013
National Category
Natural Sciences
Research subject
Natural sciences
Identifiers
urn:nbn:se:his:diva-7232 (URN)10.3892/ijo.2012.1732 (DOI)000314001000025 ()23232578 (PubMedID)2-s2.0-84873694384 (Scopus ID)
Available from: 2013-02-14 Created: 2013-02-14 Last updated: 2017-12-06Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8962-0860

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