| 1. |
- Went, M, et al.
(författare)
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Author Correction: Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 213-
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Tidskriftsartikel (refereegranskat)abstract
- The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.
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| 2. |
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| 3. |
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| 4. |
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| 5. |
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| 6. |
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| 7. |
- Went, M, et al.
(författare)
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Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 3707-
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM.
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| 8. |
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| 9. |
- Wirfält, Elisabet, et al.
(författare)
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Food sources of carbohydrates in a European cohort of adults.
- 2002
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Ingår i: Public Health Nutrition. - 1475-2727. ; 5:6B, s. 1197-1215
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To describe the average consumption of carbohydrate-providing food groups among study centres of the European Prospective Investigation into Cancer and Nutrition (EPIC). Methods: Of the 27 redefined EPIC study centres, 19 contributed subjects of both genders and eight centres female participants only (men, n=13 031; women, n=22 924, after exclusion of subjects under 35 and over 74 years of age from the original 36 900 total). Dietary data were obtained using the 24-hour recall methodology using the EPIC-SOFT software. The major sources of dietary carbohydrate were identified, and 16 food groups were examined. Results: The 10 food groups contributing most carbohydrate were bread; fruit; milk and milk products; sweet buns, cakes and pies; potato; sugar and jam; pasta and rice; vegetables and legumes; crispbread; and fruit and vegetable juices. Consumption of fruits as well as vegetables and legumes was higher in southern compared with northern centres, while soft drinks consumption was higher in the north. Italian centres had high pasta and rice consumption, but breakfast cereal, potato, and sweet buns, cakes and pies were higher in northern centres. In Sweden, lower bread consumption was balanced with a higher consumption of crispbread, and with sweet buns, cakes and pies. Overall, men consumed higher amounts of vegetables and legumes, bread, soft drinks, potatoes, pasta and rice, breakfast cereal and sugar and jam than women, but fruit consumption appeared more frequent in women. Conclusion: The study supports the established idea that carbohydrate-rich foods chosen in northern Europe are different from those in the Mediterranean region. When comparing and interpreting diet-disease relationships across populations, researchers need to consider all types of foods.
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| 10. |
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| 11. |
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| 12. |
- Bergh, G, et al.
(författare)
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Involvement of the retinoblastoma protein in monocytic and neutrophilic lineage commitment of human bone marrow progenitor cells
- 1999
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Ingår i: Blood. - 0006-4971. ; 94:6, s. 8-1971
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Tidskriftsartikel (refereegranskat)abstract
- The retinoblastoma gene product (pRb) is involved in both cell cycle regulation and cell differentiation. pRb may have dual functions during cell differentiation: partly by promoting a cell cycle brake at G(1) and also by interacting with tissue-specific transcription factors. We recently showed that pRb mediates differentiation of leukemic cell lines involving mechanisms other than the induction of G(1) arrest. In the present study, we investigated the role of pRb in differentiation of human bone marrow progenitor cells. Human bone marrow cells were cultured in a colony-forming unit-granulocyte-macrophage (CFU-GM) assay. The addition of antisense RB oligonucleotides (alpha-RB), but not the addition of sense orientated oligonucleotides (SO) or scrambled oligonucleotides (SCR), reduced the number of colonies staining for nonspecific esterase without affecting the clonogenic growth. Monocytic differentiation of CD34(+) cells supported by FLT3-ligand and interleukin-3 (IL-3) was correlated to high levels of hypophosphorylated pRb, whereas neutrophilic differentiation, supported by granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF), was correlated to low levels. The addition of alpha-RB to liquid cultures of CD34(+) cells, supported with FLT3-ligand and IL-3, inhibited monocytic differentiation. This was judged by morphology, the expression of CD14, and staining for esterase. Moreover, the inhibition of monocytic differentiation of CD34(+) cells mediated by alpha-RB, which is capable of reducing pRb expression, was counterbalanced by an enhanced neutrophilic differentiation response, as judged by morphology and the expression of lactoferrin. CD34(+) cells incubated with oligo buffer, alpha-RB, SO, or SCR showed similar growth rates. Taken together, these data suggest that pRb plays a critical role in the monocytic and neutrophilic lineage commitment of human bone marrow progenitors, probably by mechanisms that are not strictly related to control of cell cycle progression.
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| 13. |
- Birkin, Jack E., et al.
(författare)
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An ALMA/NOEMA survey of the molecular gas properties of high-redshift star-forming galaxies
- 2021
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 501:3, s. 3926-3950
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Tidskriftsartikel (refereegranskat)abstract
- We have used ALMA and NOEMA to study the molecular gas reservoirs in 61 ALMA-identified submillimetre galaxies (SMGs) in the COSMOS, UDS, and ECDFS fields. We detect 12CO (Jup = 2-5) emission lines in 50 sources, and [C I](3P1 -3P0) emission in eight, at z = 1.2-4.8 and with a median redshift of 2.9±0.2. By supplementing our data with literature sources, we construct a statistical CO spectral line energy distribution and find that the 12CO line luminosities in SMGs peak at Jup ∼ 6, consistent with similar studies. We also test the correlations of the CO, [C I], and dust as tracers of the gas mass, finding the three to correlate well, although the CO and dust mass as estimated from the 3-mm continuum are preferable. We estimate that SMGs lie mostly on or just above the star-forming main sequence, with a median gas depletion timescale, tdep = Mgas/SFR, of 210±40 Myr for our sample. Additionally, tdep declines with redshift across z ∼ 1-5, while the molecular gas fraction, μgas = Mgas/M*, increases across the same redshift range. Finally, we demonstrate that the distribution of total baryonic mass and dynamical line width, Mbaryon-σ, for our SMGs is consistent with that followed by early-type galaxies in the Coma cluster, providing strong support to the suggestion that SMGs are progenitors of massive local spheroidal galaxies. On the basis of this, we suggest that the SMG populations above and below an 870-μm flux limit of S870 ∼ 5mJy may correspond to the division between slow and fast rotators seen in local early-type galaxies.
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| 14. |
- Björnberg, F, et al.
(författare)
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Metalloproteases and serineproteases are involved in the cleavage of the two tumour necrosis factor (TNF) receptors to soluble forms in the myeloid cell lines U-937 and THP-1
- 1995
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Ingår i: Scandinavian Journal of Immunology. - 0300-9475. ; 42:4, s. 24-418
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Tidskriftsartikel (refereegranskat)abstract
- The proteolytic processing of the two TNF receptors (TNF-R55 and TNF-R75) into soluble forms was investigated in the myeloid cell lines U-937 and THP-1. Phorbol myristate acetate (PMA) rapidly stimulated release of soluble forms of both TNF-receptors. Incubations were made with PMA and protease inhibitors directed against different target protease groups. The serineprotease inhibitors TPCK and dichloroisocoumarin and the metalloprotease inhibitor 1,10-phenanthroline reduced PMA-induced release of both soluble receptor forms with about 60-70%. Furthermore, 1,10-phenanthroline also reduced PMA-induced down-regulation of TNF-receptors in both cell lines as judged by TNF-binding to cells. Reduced down-regulation and TNF-receptor shedding by 1,10-phenanthroline was reversed by Zn2+, indicating involvement of a Zn(2+)-dependent metalloprotease. Thus, both serine proteases and metalloproteases are involved in the processing of TNF-receptors.
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| 15. |
- Brattsand, G, et al.
(författare)
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Quantitative analysis of the expression and regulation of an activation-regulated phosphoprotein (oncoprotein 18) in normal and neoplastic cells.
- 1993
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Ingår i: Leukemia. - 0887-6924 .- 1476-5551. ; 7:4, s. 569-79
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Tidskriftsartikel (refereegranskat)abstract
- Activation of protein kinase C results in phosphorylation of a 19-kDa protein termed 19K. Isolation and sequence analysis of a cDNA encoding the 19K protein revealed that this protein has been studied in other systems under different names. The name oncoprotein 18 (Op18) has been proposed on the basis of a postulated up-regulation in neoplastic cells. In the present report we adopt the designation Op18 for the 19K protein, and quantify this phosphoprotein in a series of leukemia/lymphoma cell lines, a panel of non-transformed cells and some terminally differentiated cell types. For this purpose we have developed reagents allowing quantitative Western-blot analysis, and quantification of Op18 on the single cell level by flow cytometric analysis. The data demonstrates a pronounced up-regulation of the Op18 protein in most leukemia/lymphoma cell lines. The HPB-ALL cell line provided the most extreme case and expressed 7 x 10(6) Op18 molecules/cell, which compares with 0.65 x 10(6) Op18 molecules/cell in non-transformed lymphoblastoid cells. The expression of Op18 appears to be restricted to cell types with proliferative potential, but it is clear from our results that up-regulation of Op18 is uncoupled from cellular proliferation. Moreover, by employing an Epstein-Barr virus based shuttle vector, we expressed Op18 cDNA in lymphoblastoid cells. This resulted in a three to fourfold up-regulation of Op18 that did not have any detectable consequences for cell-surface phenotype or cell size. However, increased expression of Op18 resulted in a partial inhibition of cell proliferation. Taken altogether, the results suggest that up-regulation Op18 levels in leukemia/lymphoma cells are strongly associated with, but not a direct cause of tumour progression.
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| 16. |
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| 17. |
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| 18. |
- Chylicki, K, et al.
(författare)
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p53-mediated differentiation of the erythroleukemia cell line K562
- 2000
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Ingår i: Cell Growth and Differentiation. - 1044-9523. ; 11:6, s. 24-315
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Tidskriftsartikel (refereegranskat)abstract
- The tumor suppressor gene p53 can mediate both apoptosis and cell cycle arrest. In addition, p53 also influences differentiation. To further characterize the differentiation inducing properties of p53, we overexpressed a temperature-inducible p53 mutant (ptsp53Val135) in the erythroleukemia cell line K562. The results show that wild-type p53 and hemin synergistically induce erythroid differentiation of K562 cells, indicating that p53 plays a role in the molecular regulation of differentiation. However, wild-type p53 did not affect phorbol 12-myristate 13-acetate-dependent appearance of the megakaryocyte-related cell surface antigens CD9 and CD61, suggesting that p53 does not generally affect phenotypic modulation. The cyclin-dependent kinase inhibitor p21, a transcriptional target of p53, halts the cell cycle in G1 and has also been implicated in the regulation of differentiation and apoptosis. However, transiently overexpressed p21 did neither induce differentiation nor affect the cell cycle distribution or viability of K562 cells, suggesting that targets downstream of p53 other than p21 are critical for the p53-mediated differentiation response.
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| 19. |
- Ehinger, Mats, et al.
(författare)
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p53-dependent and -independent differentiation of leukemic U-937 cells : relationship to cell cycle control
- 1998
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Ingår i: Experimental Hematology. - 1873-2399. ; 26:11, s. 52-1043
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Tidskriftsartikel (refereegranskat)abstract
- Observations based on overexpression of the suppressor gene p53 or interference with endogenous p53 support a role for p53 in mediating not only growth inhibition and apoptosis but also differentiation. The aim of this study was to characterize the mechanisms of p53-dependent differentiation in the monoblastic leukemia cell line U-937. These cells were transfected with a mutant of the p53 gene expressing wild-type p53 at a permissive temperature. The results showed that wild-type p53 and interferon (IFN)-gamma were able to work synergistically to promote differentiation. This cooperative response was not associated with early G1 arrest of the cell cycle, indicating that p53 can mediate differentiation by mechanisms other than those used for mediating G1 arrest. The differentiation response to transfected p53 with or without INF-gamma was inhibited by cyclic adenosine monophosphate (cAMP)-inducing agents (dibutyryl cyclic adenosine 3':5'-monophosphate, forskolin, and 3-isobutyl-1-methylxanthine) in a dose-dependent manner. In contrast, the differentiation response of p53-negative U-937 cells to 1,25-dihydroxychole-calciferol or all-trans retinoic acid was enhanced by cAMP-inducing agents at optimal concentrations and inhibited at higher concentrations. In addition, 1,25-dihydroxycholecalciferol-mediated differentiation could be achieved in cells arrested in G1 by concomitant incubation with cAMP-inducing agents, indicating that differentiation can occur in the absence of proliferation. In conclusion, the results of this study indicate that p53-dependent and -independent differentiation can occur independently of cell cycle regulation.
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| 20. |
- Ehinger, M, et al.
(författare)
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The tumor suppressor gene p53 can mediate transforming growth [corrected] factor beta1-induced differentiation of leukemic cells independently of activation of the retinoblastoma protein
- 1997
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Ingår i: Cell Growth and Differentiation. - 1044-9523. ; 8:10, s. 37-1127
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Tidskriftsartikel (refereegranskat)abstract
- Although the involvement of the tumor suppressor gene p53 in normal hematopoiesis is uncertain, it can give rise to differentiation signals in leukemic cells. It is not clear, however, whether differentiation merely is a consequence of the ability of p53 to arrest cell proliferation or whether hitherto unknown molecular mechanisms are responsible for the p53-mediated differentiation. To further explore the role of p53 in leukemic cell differentiation, we investigated whether transforming growth factor beta1 (TGF-beta1), a cytokine involved in cell cycle control at several levels, can cooperate with wild-type p53 to induce differentiation of monoblastic U-937 and erythroleukemic K562 cells. Indeed, wild-type p53-expressing cells were found to be more sensitive to TGF-beta1-induced differentiation than control cells, lending support to the idea that p53 is of importance for differentiation induction of leukemic cells. In addition, it is shown that TGF-beta1 can suppress p53-mediated cell death, thus reinforcing the differentiation response. The cyclin-dependent kinase inhibitor p21 and the retinoblastoma protein (pRb) are downstream effectors of p53-mediated growth arrest. Therefore, the roles for these molecules in p53-mediated differentiation were examined. The p53-dependent signals of differentiation were associated with induction of p21 in both cell lines investigated. However, activation of pRb by induced hypophosphorylation and concomitant decreased growth rate on p53-mediated differentiation was observed only in U-937 cells expressing an inducible, temperature-sensitive form of p53 but not in K562 cells constitutively expressing p53. Thus, our data suggest a role for p53 in the regulation of differentiation in leukemic cells that can be independent of its ability to activate pRb and arrest cell proliferation.
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| 21. |
- Elmståhl, S., et al.
(författare)
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Dietary patterns in high and low consumers of meat in a Swedish cohort study
- 1999
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Ingår i: Appetite. - : Elsevier BV. - 0195-6663. ; 32:2, s. 191-206
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Tidskriftsartikel (refereegranskat)abstract
- The objective was to examine relationships between meat and other food items which have been associated with higher risk of cancer in the colon and prostate in some epidemiological studies. The study was conducted as a population-based cohort study comprising 11648 subjects (4816 male and 6742 female) born between 1926 and 1945 and living in the city of Malmo, Sweden. Data on mean daily intake of foods and nutrients were assessed with a diet history method combining a 7-day menu book and a food frequency questionnaire. Increasing meat intake, expressed in quintiles and adjusted for energy, was associated with decreasing intakes of poultry, fish, fruits, bread, cereals and cheese in both sexes. Low negative correlations between meat intake and ascorbic acid (r = -0.11) and fiber (r = -0.16 to -0.20) were noted. The average intake of fat from meat out of total fat intake was 13.6% in men and 11.9% in women. No major associations were noted between meat and the cholesterol raising fatty acids C:12:0, C:14:0, C:160 nor for C:20:4 or its precursor C:18:2. In conclusion, our findings indicate that meat consumption is negatively associated with food groups rich in antioxidants and fiber and the positive covariance reported between meat and cancer and coronary heart disease might, therefore, not be directly linked to components in meat.
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| 22. |
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| 23. |
- Fynbo, J. P. U., et al.
(författare)
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Galaxy counterparts of metal-rich damped Ly alpha absorbers - I. The case of the z=2.35 DLA towards Q2222-0946
- 2010
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 408:4, s. 2128-2136
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Tidskriftsartikel (refereegranskat)abstract
- We have initiated a survey using the newly commissioned X-shooter spectrograph to target candidate relatively metal-rich damped Ly alpha absorbers (DLAs). Our rationale is that high-metallicity DLAs due to the luminosity-metallicity relation likely will have the most luminous galaxy counterparts. In addition, the spectral coverage of X-shooter allows us to search for not only Ly alpha emission, but also rest-frame optical emission lines. We have chosen DLAs where the strongest rest-frame optical lines ([O II], [O III], H beta and H alpha) fall in the near-infrared atmospheric transmission bands. In this first paper resulting from the survey, we report on the discovery of the galaxy counterpart of the z(abs) = 2.354 DLA towards the z = 2.926 quasar Q2222-0946. This DLA is amongst the most metal-rich z > 2 DLAs studied so far at comparable redshifts and there is evidence for substantial depletion of refractory elements on to dust grains. We measure metallicities from Zn II, Si II, Ni II, Mn II and Fe II of -0.46 +/- 0.07, -0.51 +/- 0.06, -0.85 +/- 0.06, -1.23 +/- 0.06 and -0.99 +/- 0.06, respectively. The galaxy is detected in the Ly alpha, [O III] lambda lambda 4959, 5007 and H alpha emission lines at an impact parameter of about 0.8 arcsec (6 kpc at z(abs) = 2.354). Based on the H alpha line, we infer a star formation rate of 10M(circle dot) yr(-1), which is a lower limit due to the possibility of slit loss. Compared to the recently determined H alpha luminosity function for z = 2.2 galaxies, the DLA-galaxy counterpart has a luminosity of L similar to 0.1L*(H alpha). The emission-line ratios are 4.0 (Ly alpha/H alpha) and 1.2 ([O III]/H alpha). In particular, the Ly alpha line shows clear evidence for resonant scattering effects, namely an asymmetric, redshifted (relative to the systemic redshift) component and a much weaker blueshifted component. The fact that the blueshifted component is relatively weak indicates the presence of a galactic wind. The properties of the galaxy counterpart of this DLA are consistent with the prediction that metal-rich DLAs are associated with the most luminous of the DLA-galaxy counterparts.
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| 24. |
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| 25. |
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| 26. |
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| 27. |
- Gullberg, U, et al.
(författare)
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Biosynthesis, processing and sorting of neutrophil proteins : insight into neutrophil granule development
- 1997
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 58:3, s. 137-153
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophil granulocytes are specialized phagocytic cells that carry a collection of granules for regulated secretion, each with distinct constituents. The granules can be classified as azurophil (primary), developed first, followed in time by specific (secondary) granules gelatinase granules, and secretory vesicles. Stage- and tissue-specific transcription factors govern the successive expression of genes for granule proteins to allow storage of the gene products in these organelle categories whose packaging is separated in time. Many of the granule proteins, in particular those of the heterogeneous lysosome-like azurophil granules, are subject to extensive post-translational proteolytic processing into mature proteins, most commonly as a post-sorting event. A selective aggregation of proteins destined for storage in granules, as discussed in this review, would facilitate their retention and eliminate a need for distinct sorting motifs on each granule protein. Aggregation of granule proteins, that are often cationic, would be assisted by the anionic serglycin proteoglycans present in neutrophils. The antibacterial granule proteins can serve as models for antibiotics and some of them possess a potentially useful therapeutic ability to bind and neutralize endotoxin. Because aberrant expression of transcription factors regulating the synthesis of granule proteins is often found in leukemia, the clarification of mechanisms regulating the timed expression of granule proteins will shed light on the maturation block in myeloid leukemias.
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| 28. |
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| 29. |
- Gullberg, U, et al.
(författare)
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Receptors for hematopoietic regulatory cytokines : overview of structure and function
- 1995. - 1
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Ingår i: Cytokines: : Interleukins and Their Receptors - Interleukins and Their Receptors. - Boston, MA : Springer US. - 0927-3042. - 9780792336365 - 9781461312413 ; 80, s. 1-24
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Bokkapitel (refereegranskat)abstract
- The production of blood cells is regulated by the action of external factors, cytokines, that can be released by many cell types. In the first place, a population of multipotent stem cells, mostly in the resting Go phase of the cell cycle, but with self-renewal capacity, gives rise to progenitor cells that are predetermined for differentiation into all kinds of blood cells. Expression of genes for cytokine receptors leads to external regulation of hematopoiesis by cytokines which bind to the receptors, resulting in modifications of proliferation and differentiation, as cytokines are not only growth factors, but are also maturation factors capable of directing hematopoiesis towards functionally competent cells. What is more, they are survival factors capable of suppressing programmed cell death (apoptosis). This is of particular importance for the viability of stem cells which must be preserved. Thus cytokines can act at all positions of the hematopoietic family tree, and the response can differ from proliferation and differentiation of progenitor cells to functional activation of mature cells. Under physiological conditions, during constitutive hematopoiesis, the regulatory cytokines are produced locally, for instance by stromal ceils of the microenvironment, and act locally in a paracrine manner [2].
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| 30. |
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| 31. |
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| 32. |
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| 33. |
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| 34. |
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| 35. |
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| 36. |
- Kusche-Gullberg, M., et al.
(författare)
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Heparan Sulfate GlcA/GlcNAc Transferases
- 2001
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Ingår i: Handbook of Glycosyltransferases and Their Related Genes. - : Taniguchi, N., ed..
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 37. |
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| 38. |
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| 39. |
- Luttens, Andreas, et al.
(författare)
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Ultralarge Virtual Screening Identifies SARS-CoV-2 Main Protease Inhibitors with Broad-Spectrum Activity against Coronaviruses
- 2022
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 144:7, s. 2905-2920
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Tidskriftsartikel (refereegranskat)abstract
- Drugs targeting SARS-CoV-2 could have saved millions of lives during the COVID-19 pandemic, and it is now crucial to develop inhibitors of coronavirus replication in preparation for future outbreaks. We explored two virtual screening strategies to find inhibitors of the SARS-CoV-2 main protease in ultralarge chemical libraries. First, structure-based docking was used to screen a diverse library of 235 million virtual compounds against the active site. One hundred top-ranked compounds were tested in binding and enzymatic assays. Second, a fragment discovered by crystallographic screening was optimized guided by docking of millions of elaborated molecules and experimental testing of 93 compounds. Three inhibitors were identified in the first library screen, and five of the selected fragment elaborations showed inhibitory effects. Crystal structures of target-inhibitor complexes confirmed docking predictions and guided hit-to-lead optimization, resulting in a noncovalent main protease inhibitor with nanomolar affinity, a promising in vitro pharmacokinetic profile, and broad-spectrum antiviral effect in infected cells.
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| 40. |
- Marklund, U, et al.
(författare)
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Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase.
- 1993
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 268:20
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Tidskriftsartikel (refereegranskat)abstract
- Oncoprotein 18 (Op18) is an 18-19-kDa cytoplasmic phosphoprotein, of unknown function, that is frequently up-regulated in transformed cells. Stimulation of various cell-surface receptors results in extensive phosphorylation of Op18 and this protein has, therefore, previously been implicated in intracellular signaling. In the present study, by expression of specific Op18 cDNA mutant constructs and phosphopeptide mapping, we have identified in vivo phosphorylation sites. In conjunction with in vitro phosphorylation experiments, using purified wild-type and mutant Op18 proteins in combination with a series of kinases, these results have identified two distinct proline-directed kinase families that phosphorylate Op18 with overlapping but distinct site preference. These two kinase families, mitogen activated protein (MAP) kinases and cyclin dependent cdc2 kinases, are involved in receptor and cell cycle-regulated phosphorylation events, respectively. Therefore, Op18 may reside at a junction where receptor and cell cycle-regulated kinase families interact with the same substrate. The present study shows that the MAP kinase has a 20-fold preference for Ser25 as opposed to Ser38 of Op18, while cdc2 kinases have a 5-fold preference for the Ser38 residue. Only a minor fraction of the 4.5 x 10(6) Op18 molecules/cell in a leukemic T-cell line are normally in their Ser25 phosphorylated form. However, antigen receptor stimulation of this cell line is shown to result in a rapid conversion of 35-45% of all Op18 molecules to the Ser25 phosphorylated form. These results suggest that Ser25 of Op18 may be a major cytoplasmic target for the MAP kinase in cells with high expression of Op18.
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| 41. |
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| 42. |
- Olsson, I, et al.
(författare)
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Cell differentiation in acute myeloid leukemia
- 1996
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 57:1, s. 1-16
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Forskningsöversikt (refereegranskat)abstract
- Acute myeloid leukemia (AML) is characterized by a differentiation block leading to accumulation of immature cells. Chromosomal translocations in AML affect transcription factors that are involved in regulation of myeloid differentiation. Aberrant expression of these factors interferes with differentiation events and has a role in the pathogenesis of AML through superactivation or (dominant negative) repression of genes regulating proliferation and differentiation or by interference with assembly of the transcription complex for these genes. The maturation arrest can be reversed by certain agents as judged by results from investigations of myeloid leukemic cell lines and from treatment of acute promyelocytic leukemia (APL) patients with all-trans retinoic acid. Inactivation of the p53 and retinoblastoma (Rb) tumor suppressor genes is also associated with the pathogenesis of leukemia through effects on the cell cycle, and manipulation of these genes can affect differentiation of AML cells. With differentiation therapy, when successful as in APL, the leukemic cell mass is reduced to allow restoration of normal hematopoiesis and clinical remission, but the disease is not cured. However, initial reduction of the cell mass by maturation can increase the probability for cure with chemotherapy. Overexpression of suppressor genes may increase the probability for differentiation. Most probably, particular molecular defects of subgroups of AML have to be explored to find optimal strategies for treatment including both blocking the cell cycle, promoting terminal differentiation, and inducing apoptosis as well as strengthening the immune response.
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| 43. |
- Richter, J, et al.
(författare)
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TNF-induced superoxide anion production in adherent human neutrophils involves both the p55 and p75 TNF receptor
- 1995
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Ingår i: Journal of Immunology. - 0022-1767. ; 154:8, s. 9-4142
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Tidskriftsartikel (refereegranskat)abstract
- TNF, a potent activator of neutrophil granulocytes, acts via two cell-surface receptors: the p55-TNF receptor (TNF-R55) and the p75-TNF receptor (TNF-R75), which can be cleaved from the cell surface and thus form soluble TNF-binding proteins (TNF-BP). The role of the two receptors in activation of the neutrophil respiratory burst was investigated. Two mAbs reacting with TNF-R55 (H398 and TBP2) induced O2 release in a similar manner but to a lesser extent than TNF. TBP2, however, required preincubation at 4 degrees C to exert its effect. Preincubation of neutrophils (both at 4 and 37 degrees C) with mAb to TNF-R75 decreased TNF-induced superoxide anion production by 67 and 64%, respectively, indicating the essential role also for TNF-R75 in neutrophil activation. This inhibitory effect could not be explained by cross-down-regulation of TNF-R55 because the TNF-R75 mAb had no effect on TNF binding to TNF-R55 as determined by binding of 125I-labeled TNF or release of TNF-R55-BP as measured by ELISA. Furthermore, the TNF-R75 mAb did not decrease superoxide anion generation induced by the TNF-R55 mAb H398, thus ruling out that the inhibitory effect of the TNF-R75 mAb is due to inhibition of the signaling pathway downstream of TNF-R55. In contrast to the TNF-R75 mAb, TNF-R55 mAbs induced down-regulation of TNF-R75 and shedding of both TNF-R55-BP and TNF-R75-BP. We conclude that both TNF-R55 and TNF-R75 are involved in TNF-induced activation of the neutrophil respiratory burst.
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| 44. |
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- Smail, Ian, et al.
(författare)
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An ALMA survey of the S2CLS UDS field: optically invisible submillimetre galaxies
- 2021
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 502:3, s. 3426-3435
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Tidskriftsartikel (refereegranskat)abstract
- We analyse a robust sample of 30 near-infrared-faint (K-AB > 25.3, 5 sigma) submillimetre galaxies (SMGs) selected from a 0.96 deg(2) field to investigate their properties and the cause of their faintness in optical/near-infrared wavebands. Our analysis exploits precise identifications based on Atacama Large Millimeter Array (ALMA) 870-mu m continuum imaging, combined with very deep near-infrared imaging from the UKIDSS Ultra Deep Survey. We estimate that SMGs with K-AB > 25.3 mag represent 15 +/- 2 per cent of the total population brighter than S-870 = 3.6 mJy, with a potential surface density of similar to 450 deg(-2) above S870 >= 1 mJy. As such, they pose a source of contamination in surveys for both high-redshift 'quiescent' galaxies and very high redshift Lyman-break galaxies. We show that these K-faint SMGs represent the tail of the broader submillimetre population, with comparable dust and stellar masses to K-AB <= 25.3 mag SMGs, but lying at significantly higher redshifts (z = 3.44 +/- 0.06 versus z = 2.36 +/- 0.11) and having higher dust attenuation (A(V) = 5.2 +/- 0.3 versus A(V) = 2.9 +/- 0.1). We investigate the origin of the strong dust attenuation and find indications that these K-faint galaxies have smaller dust continuum sizes than the K-AB <= 25.3 mag galaxies, as measured by ALMA, which suggests their high attenuation is related to their compact sizes. We identify a correlation of dust attenuation with star formation rate surface density (Sigma(SFR)), with the K-faint SMGs representing the higher Sigma(SFR) and highest A(V) galaxies. The concentrated, intense star formation activity in these systems is likely to be associated with the formation of spheroids in compact galaxies at high redshifts, but as a result of their high obscuration these galaxies are completely missed in ultraviolet, optical, and even near-infrared surveys.
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