| 1. |
- Hansson, EM, et al.
(author)
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Control of Notch-ligand endocytosis by ligand-receptor interaction
- 2010
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In: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 123:17Pt 17, s. 2931-2942
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Journal article (peer-reviewed)abstract
- In Notch signaling, cell-bound ligands activate Notch receptors on juxtaposed cells, but the relationship between ligand endocytosis, ubiquitylation and ligand-receptor interaction remains poorly understood. To study the specific role of ligand-receptor interaction, we identified a missense mutant of the Notch ligand Jagged1 (Nodder, Ndr) that failed to interact with Notch receptors, but retained a cellular distribution that was similar to wild-type Jagged1 (Jagged1WT) in the absence of active Notch signaling. Both Jagged1WT and Jagged1Ndr interacted with the E3 ubiquitin ligase Mind bomb, but only Jagged1WT showed enhanced ubiquitylation after co-culture with cells expressing Notch receptor. Cells expressing Jagged1WT, but not Jagged1Ndr, trans-endocytosed the Notch extracellular domain (NECD) into the ligand-expressing cell, and NECD colocalized with Jagged1WT in early endosomes, multivesicular bodies and lysosomes, suggesting that NECD is routed through the endocytic degradation pathway. When coexpressed in the same cell, Jagged1Ndr did not exert a dominant-negative effect over Jagged1WT in terms of receptor activation. Finally, in Jag1Ndr/Ndr mice, the ligand was largely accumulated at the cell surface, indicating that engagement of the Notch receptor is important for ligand internalization in vivo. In conclusion, the interaction-dead Jagged1Ndr ligand provides new insights into the specific role of receptor-ligand interaction in the intracellular trafficking of Notch ligands.
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| 2. |
- Marklund, U, et al.
(author)
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Domain-specific control of neurogenesis achieved through patterned regulation of Notch ligand expression
- 2010
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In: Development (Cambridge, England). - : The Company of Biologists. - 1477-9129 .- 0950-1991. ; 137:3, s. 437-445
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Journal article (peer-reviewed)abstract
- Homeodomain (HD) transcription factors and components of the Notch pathway [Delta1 (Dll1), Jagged1 (Jag1) and the Fringe (Fng) proteins] are expressed in distinct progenitor domains along the dorsoventral (DV) axis of the developing spinal cord. However, the internal relationship between these two regulatory pathways has not been established. In this report we show that HD proteins act upstream of Notch signalling. Thus, HD proteins control the spatial distribution of Notch ligands and Fng proteins, whereas perturbation of the Notch pathway does not affect the regional expression of HD proteins. Loss of Dll1 or Jag1 leads to a domain-specific increase of neuronal differentiation but does not affect the establishment of progenitor domain boundaries. Moreover, gain-of-function experiments indicate that the ability of Dll1 and Jag1 to activate Notch is limited to progenitors endogenously expressing the respective ligand. Fng proteins enhance Dll1-activated Notch signalling and block Notch activation mediated by Jag1. This finding, combined with the overlapping expression of Fng with Dll1 but not with Jag1, is likely to explain the domain-specific activity of the Notch ligands. This outcome is opposite to the local regulation of Notch activity in most other systems, including the Drosophila wing, where Fng co-localizes with Jagged/Serrate rather than Dll/Delta, which facilitates Notch signalling at regional boundaries instead of within domains. The regulation of Notch activation in the spinal cord therefore appears to endow specific progenitor populations with a domain-wide autonomy in the control of neurogenesis and prevents any inadequate activation of Notch across progenitor domain boundaries.
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| 3. |
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| 4. |
- Fedirko, V., et al.
(author)
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Consumption of fish and meats and risk of hepatocellular carcinoma: the European Prospective Investigation into Cancer and Nutrition (EPIC)
- 2013
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In: Annals of Oncology. - : Elsevier BV. - 1569-8041 .- 0923-7534. ; 24:8, s. 2166-2173
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Journal article (peer-reviewed)abstract
- While higher intake of fish and lower consumption of red/processed meats have been suggested to play a protective role in the etiology of several cancers, prospective evidence for hepatocellular carcinoma (HCC) is limited, particularly in Western European populations. The associations of fish and meats with HCC risk were analyzed in the EPIC cohort. Between 1992 and 2010, 191 incident HCC were identified among 477 206 participants. Baseline diet was assessed using validated dietary questionnaires. A single 24-h diet recall from a cohort subsample was used for calibration. Multivariable proportional hazard regression was utilized to estimate hazard ratios (HR) and 95% confidence intervals (CI). In a nested case-control subset (HCC = 122), HBV/HCV status and liver function biomarkers were measured. HCC risk was inversely associated with intake of total fish (per 20 g/day increase, HR = 0.83, 95% CI 0.74-0.95 and HR = 0.80, 95% CI 0.69-0.97 before and after calibration, respectively). This inverse association was also suggested after adjusting for HBV/HCV status and liver function score (per 20-g/day increase, RR = 0.86, 95% CI 0.66-1.11 and RR = 0.74, 95% CI 0.50-1.09, respectively) in a nested case-control subset. Intakes of total meats or subgroups of red/processed meats, and poultry were not associated with HCC risk. In this large European cohort, total fish intake is associated with lower HCC risk.
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| 5. |
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| 6. |
- Hjelmevoll, Stig Ove, et al.
(author)
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Appropriate Time for Test-of-Cure when Diagnosing Gonorrhoea with a Nucleic Acid Amplification Test
- 2012
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In: Acta Dermato-Venereologica. - Uppsala : Acta Dermato-Venereologica. - 0001-5555 .- 1651-2057. ; 92:3, s. 316-319
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Journal article (peer-reviewed)abstract
- Culture is commonly regarded as the gold standard for diagnosis of Neisseria gonorrhoeae. However, nucleic acid amplification tests (NAATs) have rapidly replaced culture for diagnostics in many settings. The aim of the present study was to investigate the appropriate time for test-of-cure (TOC) when NAATs are used for diagnosis of gonorrhoea. In total, 30 patients (28 men and 2 women) provided urethral, cervical, rectal or pharyngeal specimens for TOC. All included patients, except one who did not return for second TOC before day 19, tested negative within 2 weeks after treatment with cefixime 400 mg x 1. Antimicrobial susceptibility testing showed that 68% of the culture-positive strains were resistant to ciprofloxacin. Thus, the recommended empirical treatment with ciprofloxacin in Norway should be changed immediately. TOC can be performed 2 weeks after treatment when NAATs are used for diagnosis of gonorrhoea.
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| 7. |
- Lek, M, et al.
(author)
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A homeodomain feedback circuit underlies step-function interpretation of a Shh morphogen gradient during ventral neural patterning
- 2010
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In: Development (Cambridge, England). - : The Company of Biologists. - 1477-9129 .- 0950-1991. ; 137:23, s. 4051-4060
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Journal article (peer-reviewed)abstract
- The deployment of morphogen gradients is a core strategy to establish cell diversity in developing tissues, but little is known about how small differences in the concentration of extracellular signals are translated into robust patterning output in responding cells. We have examined the activity of homeodomain proteins, which are presumed to operate downstream of graded Shh signaling in neural patterning, and describe a feedback circuit between the Shh pathway and homeodomain transcription factors that establishes non-graded regulation of Shh signaling activity. Nkx2 proteins intrinsically strengthen Shh responses in a feed-forward amplification and are required for ventral floor plate and p3 progenitor fates. Conversely, Pax6 has an opposing function to antagonize Shh signaling, which provides intrinsic resistance to Shh responses and is important to constrain the inductive capacity of the Shh gradient over time. Our data further suggest that patterning of floor plate cells and p3 progenitors is gated by a temporal switch in neuronal potential, rather than by different Shh concentrations. These data establish that dynamic, non-graded changes in responding cells are essential for Shh morphogen interpretation, and provide a rationale to explain mechanistically the phenomenon of cellular memory of morphogen exposure.
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| 8. |
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| 9. |
- Zamora-Ros, R., et al.
(author)
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Flavonoid and lignan intake in relation to bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study
- 2014
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In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 111:9, s. 1870-1880
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Journal article (peer-reviewed)abstract
- Background: There is growing evidence of the protective role of dietary intake of flavonoids and lignans on cancer, but the association with bladder cancer has not been thoroughly investigated in epidemiological studies. We evaluated the association between dietary intakes of total and subclasses of flavonoids and lignans and risk of bladder cancer and its main morphological type, urothelial cell carcinoma (UCC), within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Methods: A cohort of 477 312 men and women mostly aged 35-70 years, were recruited in 10 European countries. At baseline, dietary flavonoid and lignan intakes were estimated using centre-specific validated questionnaires and a food composition database based on the Phenol-Explorer, the UK Food Standards Agency and the US Department of Agriculture databases. Results: During an average of 11 years of follow-up, 1575 new cases of primary bladder cancer were identified, of which 1425 were UCC (classified into aggressive (n = 430) and non-aggressive (n = 413) UCC). No association was found between total flavonoid intake and bladder cancer risk. Among flavonoid subclasses, significant inverse associations with bladder cancer risk were found for intakes of flavonol (hazard ratio comparing fifth with first quintile (HRQ5-Q1) 0.74, 95% confidence interval (CI): 0.61-0.91; P-trend = 0.009) and lignans (HRQ5-Q 10.78, 95% CI: 0.62-0.96; P-trend = 0.046). Similar results were observed for overall UCC and aggressive UCC, but not for non-aggressive UCC. Conclusions: Our study suggests an inverse association between the dietary intakes of flavonols and lignans and risk of bladder cancer, particularly aggressive UCC.
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