| 1. |
- Carén, Helena, 1979, et al.
(författare)
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High incidence of DNA mutations and gene amplifications of the ALK gene in advanced sporadic neuroblastoma tumours.
- 2008
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Ingår i: The Biochemical journal. - : Portland Press Ltd.. - 1470-8728 .- 0264-6021. ; 416:2, s. 153-9
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Tidskriftsartikel (refereegranskat)abstract
- ALK (anaplastic lymphoma kinase) is oncogenic in several tumours and has recently been identified as a predisposition gene for familial NB (neuroblastoma) harbouring mutations in the TKD (tyrosine kinase domain). We have analysed a large set of sporadic human NB primary tumours of all clinical stages for chromosomal re-arrangements using a CGH (comparative genomic hybridization) array (n=108) and mutations of the ALK gene (n=90), and expression of ALK and related genes (n=19). ALK amplification or in-gene re-arrangements were found in 5% of NB tumours and mutations were found in 11%, including two novel not previously published mutations in the TKD, c.3733T>A and c.3735C>A. DNA mutations in the TKD and gene amplifications were only found in advanced large primary tumours or metastatic tumours, and correlated with the expression levels of ALK and downstream genes as well as other unfavourable features, and poor outcome. The results of the present study support that the ALK protein contributes to NB oncogenesis providing a highly interesting putative therapeutic target in a subset of unfavourable NB tumours.
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| 2. |
- Frick, Anna, 1982, et al.
(författare)
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Mercury increases water permeability of a plant aquaporin through a non-cysteine-related mechanism
- 2013
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Ingår i: Biochemical Journal. - : Portland Press Ltd.. - 0264-6021 .- 1470-8728. ; 454:pt 3, s. 491-499
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Tidskriftsartikel (refereegranskat)abstract
- Water transport across cellular membranes is mediated by a family of membrane proteins known as AQPs (aquaporins). AQPs were first discovered on the basis of their ability to be inhibited by mercurial compounds, an experiment which has followed the AQP field ever since. Although mercury inhibition is most common, many AQPs are mercury insensitive. In plants, regulation of AQPs is important in order to cope with environmental changes. Plant plasma membrane AQPs are known to be gated by phosphorylation, pH and Ca2+. We have previously solved the structure of the spinach AQP SoPIP2;1 (Spinacia oleracea plasma membrane intrinsic protein 2; 1) in closed and open conformations and proposed a mechanism for how this gating can be achieved. To study the effect of mercury on SoPIP2; 1 we solved the structure of the SoPIP2;1-mercury complex and characterized the water transport ability using proteoliposomes. The structure revealed mercury binding to three out of four cysteine residues. In contrast to what is normally seen for AQPs, mercury increased the water transport rate of SoPIP2; 1, an effect which could not be attributed to any of the cysteine residues. This indicates that other factors might influence the effect of mercury on SoPIP2; 1, one of which could be the properties of the lipid bilayer.
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| 3. |
- Holtta-Vuori, M., et al.
(författare)
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Zebrafish: gaining popularity in lipid research
- 2010
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Ingår i: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 429:2, s. 235-242
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Tidskriftsartikel (refereegranskat)abstract
- Zebrafish are an increasingly popular vertebrate model organism in which to study biological phenomena. It has been widely used, especially ill developmental biology and neurobiology, and many aspects of its development and physiology are similar to those of mammals. The popularity of zebrafish relies on its relatively low cost, rapid development and ease of genetic manipulation. Moreover, the optical transparency of the developing fish together with novel imaging techniques enable the direct visualization of complex phenomena at the level of the entire organism. This potential is now also being increasingly appreciated by the lipid research community. In the present review we summarize basic information on the lipid composition and distribution in zebrafish tissues, including lipoprotein metabolism, intestinal lipid absorption, the yolk lipids and their mobilization, as well as lipids in the nervous system. We also discuss studies in which zebrafish have been employed for the visualization of whole-body lipid distribution and trafficking. Finally, recent advances in using zebrafish as a model for lipid-related diseases, including atherosclerosis, obesity, diabetes and hepatic steatosis are highlighted. As the insights into zebrafish lipid metabolism increase, it is likely that zebrafish as a model organism will become an increasingly powerful tool in lipid research.
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| 4. |
- Liu, Ning, et al.
(författare)
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Transcriptional regulation mechanisms of hypoxia-induced neuroglobin gene expression.
- 2012
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Ingår i: The Biochemical journal. - 1470-8728 .- 0264-6021. ; 443:1, s. 153-164
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Tidskriftsartikel (refereegranskat)abstract
- Ngb (neuroglobin) has been identified as a novel endogenous neuroprotectant. However, little is known about the regulatory mechanisms of Ngb expression, especially under conditions of hypoxia. In the present study, we located the core proximal promoter of the mouse Ngb gene to a 554 bp segment, which harbours putative conserved NF-κB (nuclear factor κB)- and Egr1 (early growth-response factor 1) -binding sites. Overexpression and knockdown of transcription factors p65, p50, Egr1 or Sp1 (specificity protein 1) increased and decreased Ngb expression respectively. Experimental assessments with transfections of mutational Ngb gene promoter constructs, as well as EMSA (electrophoretic mobility-shift assay) and ChIP (chromatin immunoprecipitation) assays, demonstrated that NF-κB family members (p65, p50 and cRel), Egr1 and Sp1 bound in vitro and in vivo to the proximal promoter region of the Ngb gene. Moreover, a κB3 site was found as a pivotal cis-element responsible for hypoxia-induced Ngb promoter activity. NF-κB (p65) and Sp1 were also responsible for hypoxia-induced up-regulation of Ngb expression. Although there are no conserved HREs (hypoxia-response elements) in the promoter of the mouse Ngb gene, the results of the present study suggest that HIF-1α (hypoxia-inducible factor-1α) is also involved in hypoxia-induced Ngb up-regulation. In conclusion, we have identified that NF-κB, Egr1 and Sp1 played important roles in the regulation of basal Ngb expression via specific interactions with the mouse Ngb promoter. NF-κB, Sp1 and HIF-1α contributed to the up-regulation of mouse Ngb gene expression under hypoxic conditions.
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| 5. |
- Sörensson, Carolin, et al.
(författare)
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Determination of primary sequence specificity of Arabidopsis MAPKs MPK3 and MPK6 leads to identification of new substrates
- 2012
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Ingår i: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 446, s. 271-278
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Tidskriftsartikel (refereegranskat)abstract
- MAPKs (mitogen-activated protein kinases) are signalling components highly conserved among eukaryotes. Their diverse biological functions include cellular differentiation and responses to different extracellular stress stimuli. Although some substrates of MAPKs have been identified in plants, no information is available about whether amino acids in the primary sequence other than proline-directed phosphorylation (pS-P) contribute to kinase specificity towards substrates. in the present study, we used a random positional peptide library to search for consensus phosphorylation sequences for Arabidopsis MAPKs MPK3 and MPK6. These experiments indicated a preference towards the sequence L/P-P/X-S-P-R/K for both kinases. After bioinformatic processing, a number of novel candidate MAPK substrates were predicted and subsequently confirmed by in vitro kinase assays using bacterially expressed native Arabidopsis proteins as substrates. MPK3 and MPK6 phosphorylated all proteins tested more efficiently than did another MAPK, MPK4. These results indicate that the amino acid residues in the primary sequence surrounding the phosphorylation site of Arabidopsis MAPK substrates can contribute to MAPK specificity. Further characterization of one of these new substrates confirmed that AtIg80180.1 was phosphorylated in planta in a MAPK-dependent manner. Phenotypic analyses of Arabidopsis expressing phosphorylation site mutant forms of AtIg80180.1 showed clustered stomata and higher stomatal index in cotyledons expressing the phosphomimetic form of AtIg80180.1, providing a link between this new MAPK substrate and the defined role for MPK3 and MPK6 in stomatal patterning.
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