| 1. |
- Andersson, Christian X, 1973, et al.
(author)
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Shedding and gamma-Secretase mediated intramembrane proteolysis of the mucin-type molecule CD43
- 2005
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In: Biochem J.. ; 387:2, s. 377-384
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Journal article (peer-reviewed)abstract
- CD43 is a transmembrane molecule that contains a 123-aminoacids-long cytoplasmic tail and a highly O-glycosylated extracellular domain of mucin type. Endogenous CD43 expressed in COLO 205, K562 and Jurkat cells revealed a membrane-associated, 20 kDa CD43-specific cytoplasmic tail fragment (CD43-CTF) upon inhibition of gamma-secretase. This fragment was formed by an extracellular cleavage, as it was not accumulated after treating cells with 1,10-phenanthroline, a metalloprotease inhibitor. When CD43 was transfected into HEK-293 cells expressing dominant-negative PS1 (presenilin-1), the CD43-CTF was accumulated, but not in cells with wild-type PS1. Owing to its accumulation in the presence of a non-functional PS variant, it may thus be a novel gamma-secretase substrate. This CTF is formed by an extracellular cleavage close to the membrane, is a fragment that can be concluded to be a substrate for gamma-secretase. However, the intracellular gamma-secretase product has not been possible to detect, suggesting a quick processing of this product. During normal growth the CTF was not found without gamma-secretase inhibition, but when the cells (COLO 205) were very confluent the fragment could be detected. The intracellular domain of CD43 has previously been shown to contain a functional nuclear localization signal, and has been suggested to be involved in gene activation. From this and the present results, a novel way to explain how mucin-type molecules may transduce intracellular signals can be proposed.
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| 2. |
- Andersson, Christian X, 1973, et al.
(author)
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CD43 has a functional NLS, interacts with beta-catenin, and affects gene expression
- 2004
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In: Biochem. Biophys. Res. Commun.. - : Elsevier BV. ; 316:1, s. 12-17
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Journal article (peer-reviewed)abstract
- CD43 is a transmembrane molecule with a highly O-glycosylated extracellular domain of mucin type. It is a normal constituent of leukocytes and found in colon adenoma, but not in normal colon epithelia. Here it is shown that the cytoplasmic tail of CD43 contains a functional bipartite nuclear localization signal directing it to the nucleus. The intracellular domain of CD43 interacts with beta-catenin and causes an upregulation of the beta-catenin target genes c-MYC and CyclinD1. The present results suggest that CD43 can be involved in nuclear signaling and via beta-catenin interaction be involved in cell proliferation.
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| 3. |
- Andersson, Christian X, 1973
(author)
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Expression and novel function of CD43 in colon cancer cells
- 2003
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Doctoral thesis (other academic/artistic)abstract
- CD43 is a transmembrane protein containing an extracellular domain that is extensively O-glycosylated, and a relatively large intracellular domain with a conserved sequence between human, rat and mouse. It is frequently expressed in haematopoietic cell lines where it functions as a regulator of cell adhesiveness, a signal transducer and a cytoskeleton-interacting protein. Previous findings by our group have shown that CD43 can also be expressed in colon adenomas and carcinomas, which led us to further investigate the function of CD43 in these types of cells. Different monoclonal antibodies against the intracellular domain of CD43 were raised and characterized. Using these antibodies, the CD43 expression was studied in several non-haematopoietic cell lines including different types of cancer cell lines. By examining the CD43 expression using immunohistochemistry, flow cytometry, RT-PCR, immunoprecipitation and western blot, we concluded that CD43 was ubiquitously expressed in all the cell lines studied, albeit at varying levels. A more detailed analysis of the CD43 expression in colon cancer cells revealed that the cytoplasmic tail of CD43 could translocate to the cell nucleus. A potential nuclear localization signal (NLS) was found in the intracellular domain of CD43, which was confirmed to be functional by mutagenesis studies. In the nucleus, co-immunoprecipitation of CD43 revealed that it could interact with the tumor-associated molecule b-catenin. b-Catenin is known to cause proliferation in colon carcinomas by escaping from the degradation pathway, entering the nucleus, binding to transcription factors and activating different oncogenes (e.g. c-MYC and Cyclin D1). Using a reporter system, the intracellular domain of CD43 was found to increase the transactivational properties of the b-catenin/TCF-4 complex and to cause an elevated level of c-MYC and Cyclin D1 protein expression. The proteolytic processing of CD43 was also studied. We found that the previously observed proteolytic release of the extracellular domain of CD43 was followed by a second intramembrane cleavage, releasing the intracellular domain of CD43. The intramembrane cleavage was found to be carried out by two separate proteolytic pathways; either the cleavage was dependent of g-secretase activity or it could occur in a g-secretase independent manner. In summary, this thesis presents results suggesting a novel function of CD43 in colon cancer cells. The results imply that CD43 can be involved in colon cancer development by entering the cell nucleus and participate in the activation of certain oncogenes.
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| 4. |
- Andersson, Christian X, 1973, et al.
(author)
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Inflamed adipose tissue, insulin resistance and vascular injury
- 2008
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In: Diabetes/Metabolism Research and Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 24:8, s. 595-603
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Journal article (peer-reviewed)abstract
- Type 2 diabetes is the most common metabolic disorder today and has reached epidemic proportions in many countries. Insulin resistance and inflammation play a central role in the pathogenesis of type 2 diabetes and are present long before the onset of the disease. During this time, many of the complications associated with type 2 diabetes are initiated. Of major concern is the two- to fourfold increase in cardiovascular morbidity and mortality in this group compared to a nondiabetic population. Obesity, characterized by enlarged fat cells, and insulin resistance are, like type 2 diabetes, associated with impaired adipogenesis and a low-grade chronic inflammation that to a large extent emanates from the adipose tissue. Both these processes contribute to unfavourable alterations of the circulating levels of several bioactive molecules (adipokines) that are secreted from the adipose tissue, many of which have documented inhibitory effects on insulin sensitivity in the liver and peripheral tissues and, in addition, have negative effects on the cardiovascular system.Here we review current knowledge of the adipose tissue as an endocrine organ, the local and systemic effects of a chronic state of low-grade inflammation residing in the adipose tissue, and, in particular, the effects of inflammation and circulating adipokines on the vascular wall.
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| 5. |
- Andersson, Christian X, 1973, et al.
(author)
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Insulin antagonizes interleukin-6 signaling and is anti-inflammatory in 3T3-L1 adipocytes
- 2007
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In: J Biol Chem. - 0021-9258. ; 282:13, s. 9430-5
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Journal article (peer-reviewed)abstract
- Adipose tissue secretes different adipokines, including interleukin-6 (IL-6), that have been implicated in the insulin resistance and inflammatory state characterizing obesity. We examined the putative cross-talk between insulin and IL-6 in adipose cells and found that insulin exerts an inhibitory effect on the IL-6 signaling pathway by altering the post-translational modifications of the signal transducer and activator of transcription 3 (STAT3). Insulin reduces the tyrosine phosphorylation and increases the serine phosphorylation of STAT3, thereby reducing its nuclear localization and transcriptional activity. Signaling through the MEK/MAPK pathway plays an important role as treatment with the MEK inhibitor PD98059 reduces the effects of insulin on IL-6 signaling. We also show that the protein tyrosine phosphatase SHP2 is activated upon insulin signaling and is required for the dephosphorylation of STAT3 and that insulin exerts a synergistic effect with IL-6 on suppressor of cytokine signaling 3 expression. As a consequence, the IL-6-induced expression of the inflammatory markers serum amyloid A 3 and haptoglobin are significantly decreased in cells incubated with both IL-6 and insulin. Thus, insulin exerts an important anti-inflammatory effect in adipose cells by impairing the IL-6 signal at several levels.
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| 6. |
- Fernandez-Rodriguez, Julia, 1965, et al.
(author)
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The leukocyte antigen CD43 is expressed in different cell lines of nonhematopoietic origin.
- 2002
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In: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. - 1010-4283. ; 23:4, s. 193-201
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Journal article (peer-reviewed)abstract
- CD43 is an abundant transmembrane sialoglycoprotein in leukocyte-type cell lines, but it has also been suggested to be present in colon adenomas and colon carcinomas. We have now shown that CD43 is expressed in a variety of cell lines of different origins (CaSKI, A549, 293, MTSV1-7, MCF7, HT-1080, Jurkat, K562, COLO 205, HT-29, Caco-2, DLD-1 and SW480). The level of expression of CD43 mRNA was analyzed by reverse transcriptase-polymerase chain reaction and that of the protein by immunoprecipitation and Western blot, flow cytometry and confocal microscopy using two monoclonal anti-CD43 antibodies (L10 and 4D2). As all cell lines expressed CD43, it is suggested that CD43 has a more fundamental function than previously believed and thus cannot be considered only as a specific leukocyte marker.
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| 7. |
- Franckhauser, S., et al.
(author)
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Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice
- 2008
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 51:7, s. 1306-16
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Journal article (peer-reviewed)abstract
- AIMS/HYPOTHESIS: IL-6 is released by the adipose tissue and increased circulating levels in obesity are associated with hyperinsulinaemia and insulin resistance. Short-term experiments suggest that increased IL-6 release by the skeletal muscle following exercise may improve insulin sensitivity. METHODS: In order to examine the effect of chronically elevated IL-6 levels, we overexpressed Il6 in skeletal muscle in mice using an electro-transfer procedure. RESULTS: Circulating IL-6 levels were increased and the animals rapidly lost both weight and body fat, but food intake was unchanged, which is consistent with the finding that IL-6 increased energy expenditure. Insulin levels were inappropriately elevated and combined with hypoglycaemia in spite of reduced 2-deoxy-D: -glucose uptake by skeletal muscle. Insulin-stimulated glucose uptake by skeletal muscles ex vivo was reduced, probably due to the decreased amounts of glucose transporter (GLUT)-4. Beta cell insulin content was increased, while apparent beta cell mass was unchanged. Circulating serum amyloid A cluster levels were increased tenfold due to a pronounced proinflammatory state in the liver with infiltration of inflammatory cells. However, no liver steatosis was found, which may be accounted for by concomitant AMP kinase activation. CONCLUSIONS/INTERPRETATION: Chronically elevated IL-6 levels lead to inappropriate hyperinsulinaemia, reduced body weight, impaired insulin-stimulated glucose uptake by the skeletal muscles and marked inflammation in the liver. Thus, the pleiotrophic effects of chronically elevated IL-6 levels preclude any obvious usefulness in treating obesity or its associated metabolic complications in man, despite the fact that weight reduction may be expected.
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| 8. |
- Gustafson, Birgit, 1951, et al.
(author)
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Inflamed Adipose Tissue: A Culprit Underlying the Metabolic Syndrome and Atherosclerosis
- 2007
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In: Arterioscler Thromb Vasc Biol. - 1524-4636. ; 27
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Journal article (peer-reviewed)abstract
- The metabolic syndrome is associated with a dysregulated adipose tissue; in part a consequence of adipose cell enlargement and the associated infiltration of macrophages. Adipose cell enlargement leads to a proinflammatory state in the cells with reduced secretion of adiponectin and with increased secretion of several cytokines and chemokines including interleukin (IL)-6, IL-8, and MCP-1. MCP-1 has been shown to play an important role for the associated recruitment of macrophages into the adipose tissue. The increased release of cytokines leads to an impaired differentiation of the preadipocytes with reduced lipid accumulation and induction of adiponectin, thus promoting ectopic lipid storage. In particular tumor necrosis factor (TNF) alpha, but also IL-6, has been shown to induce these effects in preadipocytes and this is associated with an increased Wnt signaling maintaining the cells in an undifferentiated and proinflammatory state. The proinflammatory state in the adipose tissue also leads to a local insulin resistance including an impaired inhibitory effect of insulin on FFA release. The insulin resistance further supports the proinflammatory state because insulin, by itself, is both antilipolytic and antiinflammatory by antagonizing cytokine-induced activation of STAT signaling.
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| 9. |
- Hammarstedt, Ann, 1975, et al.
(author)
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The effect of PPARgamma ligands on the adipose tissue in insulin resistance
- 2005
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In: Prostaglandins Leukot Essent Fatty Acids. - : Elsevier BV. - 0952-3278. ; 73:1, s. 65-75
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Journal article (peer-reviewed)abstract
- Insulin resistance is frequently accompanied by obesity and both obesity and type 2 diabetes are associated with a mild chronic inflammation. Elevated levels of various cytokines, such as TNF-alpha and IL-6, are typically found in the adipose tissue in these conditions. It has been suggested that many cytokines produced in the adipose tissue are derived from infiltrated inflammatory cells. However, the adipose tissue itself has proven to be an important endocrine organ, secreting several hormones and cytokines, usually referred to as adipokines. Peroxisome proliferator-activated receptor (PPAR)gamma is essential for adipocyte proliferation and differentiation. In recent years, PPARgamma and its ligands, the thiazolidinediones (TZD), have achieved great attention due to their insulin sensitizing and anti-inflammatory properties. Treatment with TZDs result in improved insulin signaling and adipocyte differentiation, increased adipose tissue influx of free fatty acids and inhibition of cytokine expression and action. As a result, PPARgamma plays a central role in maintaining a functional and differentiated adipose tissue.
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| 10. |
- Malmberg, Emily, 1978, et al.
(author)
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Bcr (breakpoint cluster region) protein binds to PDZ-domains of scaffold protein PDZK1 and vesicle coat protein Mint3.
- 2004
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In: Journal of cell science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 117:Pt 23, s. 5535-41
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Journal article (peer-reviewed)abstract
- The breakpoint cluster region protein (Bcr) is a large soluble oligomeric multidomain protein best known because of its involvement in chronic myelogenous leukemia (CML). A chromosomal translocation between its gene and that of the c-abl kinase ('Philadelphia chromosome') plays a major causative role in that malignancy. Thus most attention has been paid to the role of the protein in hemopoietic cells. However, Bcr is also expressed in other cell types including epithelia. Bcr is generally considered to be a cytoplasmic protein but in addition to its kinase and GTPase exchange and activating domains it contains potentially membrane-interacting pleckstrin homology and C2 domains as well as a PDZ-binding C terminus mediating an interaction with a PDZ-domain protein at intercellular junctions of epithelial cells. We have examined the ability of Bcr to interact with other epithelial PDZ proteins and found specific binding to both the apical PDZK1 protein and the Golgi-localized Mint3. The former is important in the organization of several apical functions and the latter in vesicular trafficking in the secretory pathway. Hence these findings extend the interactions and likely signaling impact of Bcr in epithelia from the cytosol to at least these two membrane compartments.
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