| 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. |
- Ghosheh, Nidal, 1975-, et al.
(author)
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Human Pluripotent Stem Cell-Derived Hepatocytes Show Higher Transcriptional Correlation with Adult Liver Tissue than with Fetal Liver Tissue
- 2020
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In: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 5:10, s. 4816-4827
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Journal article (peer-reviewed)abstract
- Human pluripotent stem cell-derived hepatocytes (hPSC-HEP) display many properties of mature hepatocytes, including expression of important genes of the drug metabolizing machinery, glycogen storage, and production of multiple serum proteins. To this date, hPSC-HEP do not, however, fully recapitulate the complete functionality of in vivo mature hepatocytes. In this study, we applied versatile bioinformatic algorithms, including functional annotation and pathway enrichment analyses, transcription factor binding-site enrichment, and similarity and correlation analyses, to datasets collected from different stages during hPSC-HEP differentiation and compared these to developmental stages and tissues from fetal and adult human liver. Our results demonstrate a high level of similarity between the in vitro differentiation of hPSC-HEP and in vivo hepatogenesis. Importantly, the transcriptional correlation of hPSC-HEP with adult liver (AL) tissues was higher than with fetal liver (FL) tissues (0.83 and 0.70, respectively). Functional data revealed mature features of hPSC-HEP including cytochrome P450 enzymes activities and albumin secretion. Moreover, hPSC-HEP showed expression of many genes involved in drug absorption, distribution, metabolism, and excretion. Despite the high similarities observed, we identified differences of specific pathways and regulatory players by analyzing the gene expression between hPSC-HEP and AL. These findings will aid future intervention and improvement of in vitro hepatocyte differentiation protocol in order to generate hepatocytes displaying the complete functionality of mature hepatocytes. Finally, on the transcriptional level, our results show stronger correlation and higher similarity of hPSC-HEP to AL than to FL. In addition, potential targets for further functional improvement of hPSC-HEP were also identified.
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| 3. |
- Jacobs, Kevin B, et al.
(author)
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Detectable clonal mosaicism and its relationship to aging and cancer.
- 2012
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In: Nature Genetics. - New York : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 44:6, s. 651-658
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Journal article (peer-reviewed)abstract
- In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
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| 4. |
- 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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| 5. |
- 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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| 6. |
- 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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| 7. |
- 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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| 8. |
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| 9. |
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| 10. |
- Dima, Danai, et al.
(author)
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Subcortical volumes across the lifespan : Data from 18,605 healthy individuals aged 3-90 years.
- 2022
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In: Human Brain Mapping. - : Wiley. - 1065-9471 .- 1097-0193. ; 43:1, s. 452-469
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Journal article (peer-reviewed)abstract
- Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.
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