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Palmer, Ruth H.
Alternative names
Publications (10 of 49) Show all publications
Fransson, S., Hansson, M., Ruuth, K., Djos, A., Berbegall, A., Javanmardi, N., . . . Martinsson, T. (2015). Intragenic Anaplastic Lymphoma Kinase (ALK) Rearrangements: Translocations as a Novel Mechanism of ALK Activation in Neuroblastoma Tumors. Genes, Chromosomes and Cancer, 54(2), 99-109
Open this publication in new window or tab >>Intragenic Anaplastic Lymphoma Kinase (ALK) Rearrangements: Translocations as a Novel Mechanism of ALK Activation in Neuroblastoma Tumors
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2015 (English)In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 54, no 2, p. 99-109Article in journal (Refereed) Published
Abstract [en]

Anaplastic lymphoma kinase (ALK) has been demonstrated to be deregulated in sporadic as well as in familiar cases of neuroblastoma (NB). Whereas ALK-fusion proteins are common in lymphoma and lung cancer, there are few reports of ALK rearrangements in NB indicating that ALK mainly exerts its oncogenic capacity via activating mutations and/or overexpression in this tumor type. In this study, 332 NB tumors and 13 cell lines were screened by high resolution single nucleotide polymorphism microarray. Gain of 2p was detected in 23% (60/332) of primary tumors and 46% (6/13) of cell lines, while breakpoints at the ALK locus were detected in four primary tumors and two cell lines. These were further analyzed by next generation sequencing and a targeted enrichment approach. Samples with both ALK and MYCN amplification displayed complex genomic rearrangements with multiple breakpoints within the amplicon. None of the translocations characterized in primary NB tumors are likely to result in a chimeric protein. However, immunohistochemical analysis reveals high levels of phosphorylated ALK in these samples despite lack of initial exons, possibly due to alternative transcription initiation sites. Both ALK proteins predicted to arise from such alterations and from the abnormal ALK exon 4-11 deletion observed in the CLB-BAR cell line show strong activation of downstream targets STAT3 and extracellular signal-regulated kinase (ERK) when expressed in PC12 cells. Taken together, our data indicate a novel, although rare, mechanism of ALK activation with implications for NB tumorigenesis. 

National Category
Cancer and Oncology Medical Genetics
Identifiers
urn:nbn:se:umu:diva-99211 (URN)10.1002/gcc.22223 (DOI)000346348600005 ()
Available from: 2015-04-22 Created: 2015-02-04 Last updated: 2018-06-07Bibliographically approved
Witek, B., El Wakil, A., Nord, C., Ahlgren, U., Eriksson, M., Vernersson-Lindahl, E., . . . Palmer, R. H. (2015). Targeted Disruption of ALK Reveals a Potential Role in Hypogonadotropic Hypogonadism. PLoS ONE, 10(5), Article ID e0123542.
Open this publication in new window or tab >>Targeted Disruption of ALK Reveals a Potential Role in Hypogonadotropic Hypogonadism
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0123542Article in journal (Refereed) Published
Abstract [en]

Mice lacking ALK activity have previously been reported to exhibit subtle behavioral phenotypes. In this study of ALK of loss of function mice we present data supporting a role for ALK in hypogonadotropic hypogonadism in male mice. We observed lower level of serum testosterone at P40 in ALK knock-out males, accompanied by mild disorganization of seminiferous tubules exhibiting decreased numbers of GATA4 expressing cells. These observations highlight a role for ALK in testis function and are further supported by experiments in which chemical inhibition of ALK activity with the ALK TKI crizotinib was employed. Oral administration of crizotinib resulted in a decrease of serum testosterone levels in adult wild type male mice, which reverted to normal levels after cessation of treatment. Analysis of GnRH expression in neurons of the hypothalamus revealed a significant decrease in the number of GnRH positive neurons in ALK knock-out mice at P40 when compared with control littermates. Thus, ALK appears to be involved in hypogonadotropic hypogonadism by regulating the timing of pubertal onset and testis function at the upper levels of the hypothalamic-pituitary gonadal axis.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-106607 (URN)10.1371/journal.pone.0123542 (DOI)000356768100016 ()25955180 (PubMedID)
Available from: 2015-07-28 Created: 2015-07-24 Last updated: 2018-06-07Bibliographically approved
Macagno, J. P., Vera, J. D., Yu, Y., MacPherson, I., Sandilands, E., Palmer, R., . . . Vidal, M. (2014). FAK Acts as a Suppressor of RTK-MAP Kinase Signalling in Drosophila melanogaster Epithelia and Human Cancer Cells. PLoS Genetics, 10(3), e1004262
Open this publication in new window or tab >>FAK Acts as a Suppressor of RTK-MAP Kinase Signalling in Drosophila melanogaster Epithelia and Human Cancer Cells
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2014 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 3, p. e1004262-Article in journal (Refereed) Published
Abstract [en]

Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling resulting from the overexpression of the RTKs RET and EGFR. FAK suppressed RTKs signalling in Drosophila melanogaster epithelia by impairing MAPK pathway. This regulation was also observed in MDA-MB-231 human breast cancer cells, suggesting it is a conserved phenomenon in humans. Mechanistically, FAK reduced receptor recycling into the plasma membrane, which resulted in lower MAPK activation. Conversely, increasing the membrane pool of the receptor increased MAPK pathway signalling. FAK is widely considered as a therapeutic target in cancer biology; however, it also has tumour suppressor properties in some contexts. Therefore, the FAK-mediated negative regulation of RTK/MAPK signalling described here may have potential implications in the designing of therapy strategies for RTK-driven tumours.

National Category
Biochemistry and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-91157 (URN)10.1371/journal.pgen.1004262 (DOI)000337144700070 ()
Available from: 2014-07-16 Created: 2014-07-15 Last updated: 2018-06-07Bibliographically approved
Jahns, A. C., Lundskog, B., Berg, J., Jonsson, R., McDowell, A., Patrick, S., . . . Alexeyev, O. A. (2014). Microbiology of folliculitis: a histological study of 39 cases. Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), 122(1), 25-32
Open this publication in new window or tab >>Microbiology of folliculitis: a histological study of 39 cases
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2014 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 122, no 1, p. 25-32Article in journal (Refereed) Published
Abstract [en]

Folliculitis is a common inflammatory skin syndrome. Several microbial organisms have been put forward as causative agents, but few studies visualized microbes directly in inflamed hair follicles. This retrospective study investigated bacterial and fungal colonization of inflamed hair follicles in patients with clinically diagnosed non-infectious folliculitis. Skin biopsies from 39 folliculitis patients and 27 controls were screened by fluorescence in situ hybridization (FISH) using broad-range bacterial and fungal probes and by immunofluorescence microscopy using a monoclonal antibody towards Gram-positive bacteria. Specific monoclonal and polyclonal antibodies towards Staphylococcus spp. and Propionibacterium acnes were applied for further species identification. Inflamed follicles were associated with bacterial colonization in 10 samples (26%) and fungal colonization in three samples (8%). Staphylococcus spp. were observed in inflamed follicles in seven samples (18%). Two samples were positive for P. acnes, which were identified as either type II or type IB/type III. Both Staphylococcus spp. and P. acnes were seen in macrocolonies/biofilm structures. In conclusion, one-third of patients with clinically diagnosed, non-infectious folliculitis exhibited microbial colonization with predominance of Staphylococcus spp.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2014
Keywords
Skin, folliculitis, microbiota, in situ hybridization, Propionibacterium acnes, Staphylococcus
National Category
Immunology in the medical area Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-85623 (URN)10.1111/apm.12103 (DOI)000328909100004 ()
Available from: 2014-02-10 Created: 2014-02-07 Last updated: 2018-06-08Bibliographically approved
Hugosson, F., Sjögren, C., Birve, A., Hedlund, L., Eriksson, T. & Palmer, R. H. (2014). The Drosophila Midkine/Pleiotrophin Homologues Miple1 and Miple2 Affect Adult Lifespan but Are Dispensable for Alk Signaling during Embryonic Gut Formation. PLoS ONE, 9(11), e112250
Open this publication in new window or tab >>The Drosophila Midkine/Pleiotrophin Homologues Miple1 and Miple2 Affect Adult Lifespan but Are Dispensable for Alk Signaling during Embryonic Gut Formation
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, p. e112250-Article in journal (Refereed) Published
Abstract [en]

Midkine (MDK) and Pleiotrophin (PTN) are small heparin-binding cytokines with closely related structures. The Drosophila genome harbours two genes encoding members of the MDK/PTN family of proteins, known as miple1 and miple2. We have investigated the role of Miple proteins in vivo, in particular with regard to their proposed role as ligands for the Alk receptor tyrosine kinase (RTK). Here we show that Miple proteins are neither required to drive Alk signaling during Drosophila embryogenesis, nor are they essential for development in the fruit fly. Additionally we show that neither MDK nor PTN can activate hALK in vivo when ectopically co-expressed in the fly. In conclusion, our data suggest that Alk is not activated by MDK/PTN related growth factors Miple1 and Miple 2 in vivo.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-97588 (URN)10.1371/journal.pone.0112250 (DOI)000344863100069 ()
Available from: 2015-01-04 Created: 2014-12-23 Last updated: 2018-06-07Bibliographically approved
Umapathy, G., El Wakil, A., Witek, B., Chesler, L., Danielson, L., Deng, X., . . . Hallberg, B. (2014). The kinase ALK stimulates the kinase ERK5 to promote the expression of the oncogene MYCN in neuroblastoma. Science Signaling, 7(349), ra102
Open this publication in new window or tab >>The kinase ALK stimulates the kinase ERK5 to promote the expression of the oncogene MYCN in neuroblastoma
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2014 (English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, ISSN 1945-0877 (print), Vol. 7, no 349, p. ra102-Article in journal (Refereed) Published
Abstract [en]

Anaplastic lymphoma kinase (ALK) is an important molecular target in neuroblastoma. Although tyrosine kinase inhibitors abrogating ALK activity are currently in clinical use for the treatment of ALK-positive (ALK(+)) disease, monotherapy with ALK tyrosine kinase inhibitors may not be an adequate solution for ALK(+) neuroblastoma patients. Increased expression of the gene encoding the transcription factor MYCN is common in neuroblastomas and correlates with poor prognosis. We found that the kinase ERK5 [also known as big mitogen-activated protein kinase (MAPK) 1 (BMK1)] is activated by ALK through a pathway mediated by phosphoinositide 3-kinase (PI3K), AKT, MAPK kinase kinase 3 (MEKK3), and MAPK kinase 5 (MEK5). ALK-induced transcription of MYCN and stimulation of cell proliferation required ERK5. Pharmacological or RNA interference-mediated inhibition of ERK5 suppressed the proliferation of neuroblastoma cells in culture and enhanced the antitumor efficacy of the ALK inhibitor crizotinib in both cells and xenograft models. Together, our results indicate that ERK5 mediates ALK-induced transcription of MYCN and proliferation of neuroblastoma, suggesting that targeting both ERK5 and ALK may be beneficial in neuroblastoma patients.

Place, publisher, year, edition, pages
American association for the Advancement of Science, 2014
National Category
Cell and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-96953 (URN)10.1126/scisignal.2005470 (DOI)000344145900003 ()
Available from: 2015-02-24 Created: 2014-12-05 Last updated: 2018-06-07Bibliographically approved
van Dijk, J. R., Yamazaki, Y. & Palmer, R. H. (2014). Tumour-associated mutations of PA-TM-RING ubiquitin ligases RNF167/RNF13 identify the PA domain as a determinant for endosomal localization. Biochemical Journal, 459(1), 27-36
Open this publication in new window or tab >>Tumour-associated mutations of PA-TM-RING ubiquitin ligases RNF167/RNF13 identify the PA domain as a determinant for endosomal localization
2014 (English)In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 459, no 1, p. 27-36Article in journal (Refereed) Published
Abstract [en]

Diverse cellular processes depend on endocytosis, intracellular vesicle trafficking, sorting and exocytosis, and processes that are regulated post-transcriptionally by modifications such as phosphorylation and ubiquitylation. The PA (protease-associated) domain E3 ligases, such as Godzilla(CG10277) in Drosophila melanogaster and RNF167 (RING finger protein 167) in humans, have been implicated in the regulation of cellular endosome trafficking. In the present study, we have characterized point mutations in the RING (really interesting new gene) domain of human RNF13 and RNF167, which have been identified in human tumour samples, that abrogate ubiquitin ligase activity as well as function. In the present study, we have also identified a functional role for the PA domain, which is required for endosomal localization of these proteins. Although the PA domain point mutations of RNF13 and RNF167 identified in human tumours are ligase active, the resultant mutant proteins are mislocalized within the cell. Thus the PA domain E3 ligases examined in the present study appear to require both E3 ligase activity as well as an intact PA domain to efficiently target and ubiquitylate their cellular substrates.

Keywords
E3 ubiquitin ligase, goliath, protease-associated (PA) domain, RING domain, RING finger protein 167 (RNF167)
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-88385 (URN)10.1042/BJ20131067 (DOI)000333718700003 ()
Available from: 2014-05-07 Created: 2014-05-05 Last updated: 2018-06-07Bibliographically approved
Chand, D., Yamazaki, Y., Ruuth, K., Schönherr, C., Martinsson, T., Kogner, P., . . . Hallberg, B. (2013). Cell culture and Drosophila model systems define three classes of anaplastic lymphoma kinase mutations in neuroblastoma. Disease Models and Mechanisms, 6(2), 373-382
Open this publication in new window or tab >>Cell culture and Drosophila model systems define three classes of anaplastic lymphoma kinase mutations in neuroblastoma
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2013 (English)In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 6, no 2, p. 373-382Article in journal (Refereed) Published
Abstract [en]

Neuroblastoma is a childhood extracranial solid tumor which is associated with a number of genetic changes. Included in these genetic alterations are mutations in the kinase domain of the Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase (RTK), which have been found in both somatic and familial neuroblastoma. In order to treat patients accordingly required characterisation of these mutations in terms of their response to ALK tyrosine kinase inhibitors (TKIs). Here, we report the identification and characterisation of two novel neuroblastoma ALK mutations (A1099T and 1464STOP) which we have investigated together with several previously reported but uncharacterised ALK mutations (T1087I, D1091N, T1151M, M1166R, F1174I and A1234T). In order to understand the potential role of these ALK mutations in neuroblastoma progression we have employed cell culture based systems together with the model organism Drosophila as a readout for ligand-independent activity. Mutation of ALK at position F1174I generates a gain-of-function receptor capable of activating intracellular targets, such as ERK (extracellular signal regulated kinase) and STAT3 (signal transducer and activator of transcription 3) in a ligand independent manner. Analysis of these previously uncharacterised ALK mutants and comparison with ALK(F1174) mutants suggests that ALK mutations observed in neuroblastoma fall into three classes. These are: (i) gain-of-function ligand independent mutations such as ALK(F1174), (ii) kinase-dead ALK mutants, e.g. ALK(I1250T)(Schonherr et al 2011a) or (iii) ALK mutations which are ligand-dependent in nature. Irrespective of the nature of the observed ALK mutants, in every case the activity of the mutant ALK receptors could be abrogated by the ALK inhibitor crizotinib (PF-02341066, Xalkori), albeit with differing levels of sensitivity.

Place, publisher, year, edition, pages
Cambridge, UK: The Company of Biologists Ltd, 2013
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-61265 (URN)10.1242/dmm.010348 (DOI)000317266500009 ()23104988 (PubMedID)
Available from: 2012-11-07 Created: 2012-11-07 Last updated: 2018-06-08Bibliographically approved
Yamazaki, Y., Schönherr, C., Varshney, G. K., Dogru, M., Hallberg, B. & Palmer, R. H. (2013). Goliath family E3 ligases regulate the recycling endosome pathway via VAMP3 ubiquitylation. EMBO Journal, 32(4), 524-537
Open this publication in new window or tab >>Goliath family E3 ligases regulate the recycling endosome pathway via VAMP3 ubiquitylation
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2013 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 32, no 4, p. 524-537Article in journal (Refereed) Published
Abstract [en]

Diverse cellular processes depend on endocytosis, intracellular vesicle trafficking, sorting and exocytosis, processes regulated post-transcriptionally by modifications such as phosphorylation and ubiquitylation. In addition to sorting to the lysosome, cargo is recycled to the plasma membrane via recycling endosomes. Here, we describe a role of the goliath gene family of protease-associated (PA) domain E3 ligases in regulating recycling endosome trafficking. The two Drosophila members of this family-Goliath and Godzilla(CG10277) - are located on endosomes, and both ectopic expression and loss-of-function lead to the accumulation of Rab5-positive giant endosomes. Furthermore, the human homologue RNF167 exhibits similar behaviour. We show that the soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) protein VAMP3 is a target of these ubiquitin ligases, and that recycling endosome trafficking is abrogated in response to their activity. Furthermore, mutation of the Godzilla ubiquitylation target lysines on VAMP3 abrogates the formation of enlarged endosomes induced by either Godzilla or RNF167. Thus, Goliath ubiquitin ligases play a novel role in regulating recycling endosome trafficking via ubiquitylation of the VAMP3 SNARE protein.

Place, publisher, year, edition, pages
Nature Publishing Group, 2013
Keywords
E3 ubiquitin ligase, goliath, RING domain, SNARE, VAMP3
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-68487 (URN)10.1038/emboj.2013.1 (DOI)000316467200006 ()
Available from: 2013-04-26 Created: 2013-04-22 Last updated: 2018-06-08Bibliographically approved
Popichenko, D., Hugosson, F., Sjögren, C., Dogru, M., Yamazaki, Y., Wolfstetter, G., . . . Palmer, R. H. (2013). Jeb/Alk signalling regulates the Lame duck GLI family transcription factor in the Drosophila visceral mesoderm. Development, 140(15), 3156-3166
Open this publication in new window or tab >>Jeb/Alk signalling regulates the Lame duck GLI family transcription factor in the Drosophila visceral mesoderm
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2013 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 140, no 15, p. 3156-3166Article in journal (Refereed) Published
Abstract [en]

The Jelly belly (Jeb)/Anaplastic Lymphoma Kinase (Alk) signalling pathway regulates myoblast fusion in the circular visceral mesoderm (VM) of Drosophila embryos via specification of founder cells. However, only a limited number of target molecules for this pathway are described. We have investigated the role of the Lame Duck (Lmd) transcription factor in VM development in relationship to Jeb/Alk signal transduction. We show that Alk signalling negatively regulates Lmd activity post-transcriptionally through the MEK/MAPK (ERK) cascade resulting in a relocalisation of Lmd protein from the nucleus to cytoplasm. It has previously been shown that downregulation of Lmd protein is necessary for the correct specification of founder cells. In the visceral mesoderm of lmd mutant embryos, fusion-competent myoblasts seem to be converted to 'founder-like' cells that are still able to build a gut musculature even in the absence of fusion. The ability of Alk signalling to downregulate Lmd protein requires the N-terminal 140 amino acids, as a Lmd(141-866) mutant remains nuclear in the presence of active ALK and is able to drive robust expression of the Lmd downstream target Vrp1 in the developing VM. Our results suggest that Lmd is a target of Jeb/Alk signalling in the VM of Drosophila embryos.

Keywords
Lmd, Alk, Jeb, Drosophila, Visceral muscle, Founder cell, Fusion competent myoblast
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-79229 (URN)10.1242/dev.094466 (DOI)000321864900009 ()
Available from: 2013-09-16 Created: 2013-08-13 Last updated: 2018-06-08Bibliographically approved
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