The discovery of constitutive nuclear factor-κB (NF-κB) activation in Hodgkin's lymphoma tumor cells almost two decades ago was one of the first reports that directly connected deregulated NF-κB ...signaling to human cancer. Subsequent studies demonstrated that enhanced NF-κB signaling is a common hallmark of many lymphoid malignancies, including Hodgkin lymphoma, mucosa-associated lymphoid tissue lymphoma, diffuse large B-cell lymphoma and multiple myeloma. By inducing an anti-apoptotic and pro-proliferative gene program, NF-κB is involved in lymphoma survival and growth. Identification of somatic mutations that led to activation of oncogenes and inactivation of tumor suppressor genes in the pathway revealed that specific pathogenic mechanisms are responsible for constitutive NF-κB activation in different lymphoma entities. Thus, the identification of distinct oncogenic events is reflecting the diverse cellular origins of the different lymphomas. Further, elucidation of the mechanisms that drive NF-κB in lymphoma is of high clinical relevance as it will allow the design of target-directed precision therapy. Indeed, a number of drugs that impair constitutive NF-κB activation in lymphoid malignancies are currently in preclinical or clinical development.
Constitutive activation of the antiapoptotic nuclear factor-κB (NF-κB) signaling pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL). Recurrent ...oncogenic mutations are found in the scaffold protein CARMA1 (CARD11) that connects B-cell receptor (BCR) signaling to the canonical NF-κB pathway. We asked how far additional downstream processes are activated and contribute to the oncogenic potential of DLBCL-derived CARMA1 mutants. To this end, we expressed oncogenic CARMA1 in the NF-κB negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identified recruitment of β-catenin and its destruction complex consisting of APC, AXIN1, CK1α and GSK3β to oncogenic CARMA1. Recruitment of the β-catenin destruction complex was independent of CARMA1-BCL10-MALT1 complex formation or constitutive NF-κB activation and promoted the stabilization of β-catenin. The β-catenin destruction complex was also recruited to CARMA1 in ABC DLBCL cell lines, which coincided with elevated β-catenin expression. In line, β-catenin was frequently detected in non-GCB DLBCL biopsies that rely on chronic BCR signaling. Increased β-catenin amounts alone were not sufficient to induce classical WNT target gene signatures, but could augment TCF/LEF-dependent transcriptional activation in response to WNT signaling. In conjunction with NF-κB, β-catenin enhanced expression of immunosuppressive interleukin-10 and suppressed antitumoral CCL3, indicating that β-catenin can induce a favorable tumor microenvironment. Thus, parallel activation of NF-κB and β-catenin signaling by gain-of-function mutations in CARMA1 augments WNT stimulation and is required for regulating the expression of distinct NF-κB target genes to trigger cell-intrinsic and extrinsic processes that promote DLBCL lymphomagenesis.
Sediments from the Polar Front Zone were sampled in the Indian Sector of the Antarctic Ocean as part of the French JGOFS expedition Antares 1. The first porewater distributions of O2and NO3
-and ...organic carbon data in the solid phase in this part of the ocean were used to model the recycling of organic matter in sediments. The data are described by a model containing two type of degradable organic matter with distinct reactivities. We estimate that the reactivity of the most labile organic carbon is very close to that of fresh organic matter with an averate C:N ratio of 7. We estimate that particulate organic carbon fluxes deposited at the sediment-water interface range between 0.2 and 0.8 mol C m-2 y-1, with two peaks near the Polar Front and the Subantarctic Front. The flux of organic carbon deposited at the sediment-water interface is unusually high and represents$\thicksim10-20%$of estimates primary production. From these findings, we conclude that production in the pelagic zone of this region is strongly linked to deposition and recycling in the sediment.
The discovery of constitutive nuclear factor-kB (NF-kB) activation in Hodgkins lymphoma tumor cells almost two decades ago was one of the rst reports that directly connected deregulated NF-kB ...signaling to human cancer. Subsequent studies demonstrated that enhanced NF-kB signaling is a common hallmark of many lymphoid malignancies, including Hodgkin lymphoma, mucosa-associated lymphoid tissue lymphoma, diffuse large B-cell lymphoma and multiple myeloma. By inducing an anti-apoptotic and pro-proliferative gene program, NF-kB is involved in lymphoma survival and growth. Identication of somatic mutations that led to activation of oncogenes and inactivation of tumor suppressor genes in the pathway revealed that specic pathogenic mechanisms are responsible for constitutive NF-kB activation in different lymphoma entities. Thus, the identication of distinct oncogenic events is reecting the diverse cellular origins of the different lymphomas. Further, elucidation of the mechanisms that drive NF-kB in lymphoma is of high clinical relevance as it will allow the design of target-directed precision therapy. Indeed, a number of drugs that impair constitutive NF-kB activation in lymphoid malignancies are currently in preclinical or clinical development.
During the ANTARES 1/F-JGOFS cruise (April–May 1993) concentrations of inorganic nitrogen, nitrification rates (ammonium and nitrite oxidation) and
14C carbonate incorporation by nitrifying bacteria ...were measured at 0, 50 and 100 m in the water column, and at the water-sediment interface between the polar front (52°S) and the subantarctic and subtropical fronts (42°S) in the Indian Ocean Sector of the Antarctic Ocean. The 0–100 m water layer showed a global increase of NH
4
+ (from 0.4 to 0.6 μM) and a global decrease of NO
2
− + NO
3
− (from 25 to 5 μM) along the south-north transect. Anomalies were detected for both ammonium and nitrite + nitrate concentrations in the SubTropical Front (STF) and SubAntarctic Front (SAF). Pelagic nitrifying activities (N oxidation) did not demonstrate any latitudinal gradient in the water column. In terms of integrated rates between 0 and 100 m, the nitrification increased by a factor 1.8–2 in the STF-SAF area. The N oxidation processes mostly depended on the substrate availability. For both ammonium and nitrite oxidizers the C fixation was well correlated (
r = 0.68,
p = 0.001 and
r = 0.98,
p = 0.0001, respectively) with N oxidation, in the range of 15 N (ammonium oxidizers) and 20 N (nitrite oxidizers) oxidized for 1 C incorporated. For nitrite oxidizers, C incorporation was principally influenced by temperature (
Q
10 = 1,73). From the calculation of nitrogen fluxes, the nitrifiers would be able to compete with the primary producers for the regenerated ammonium, while the flux of nitrate produced by nitrification could sustain 10 to 100% of the primary producer requirements for this nitrogen source.
In the sediment pore waters, the inorganic nitrogen compounds displayed two different latitudinal distributions. The ammonium concentrations were lower (around 4 μM) south of the 48°S than in the northern part (values reaching 10 μM in the first centimetre). The nitrite + nitrate concentrations were close to 40–45 μM at each end of the transect, and increased to 50–55 μM near 45°S. The benthic nitrification, measured from 0 to 5 cm depth in the sediment cores, showed high rates in the upper 3 cm. The rates of ammonium oxidation demonstrated a good correlation (
r = 0.64,
p = 0.0001) with the ammonium content of the interstitial water. The nitrite oxidation rates were well correlated (
r = 0.92,
p = 0.0001) with the ammonium oxidation rates. The integrated rates (0–5 cm) of ammonium oxidation were of about 35 nmol NO
2
− produced cm
−2 day
−1 in the south, and increased by a factor 1.3–1.9 after 44°S. Both ammonium and nitrite oxidation rates showed a maximum near 44°S, corresponding to the SAF-STF frontal zone.
The processes controlling preservation and recycling of particulate biogenic silica in superficial sediments must be understood before one uses biogenic silica as a proxy in paleooceanographic ...studies, and in order to compute oceanic mass balances for silica. In this respect, the Antarctic Ocean is certainly a key region due to its high productivity and export of biogenic silica. In order to quantify sedimentary fluxes and identify crucial processes that allow the preservation of biogenic silica, pore water and solid phase silica profiles were performed on sediment cores from the Southern Ocean (Indian Sector) during the ANTARES 1 cruise. In combination with solubility data reported by Van Cappellen and Qiu (1997a), a process model representing the early diagenesis of silica was developed. In this model, a dependence with depth of the kinetic constant was introduced to allow the preservation of biogenic silica in sediment porewater undersaturated with respect to that phase. Using this steady-state model, it is proposed that a proportionality of the reactivity of the biogenic silica with its settling flux is necessary to explain the observed profiles. It is then shown using this model that the preservation of biogenic silica is not a linear function of the deposited flux.
Using a modified version of this model containing an explicit term of reprecipitation, we hypothesize that reprecipitation alone cannot counterbalance dissolution and that its effect is certainly related to a decrease in either surface solubility or kinetics of dissolution.
Constitutive activation of the antiapoptotic nuclear factor-B (NF-B) signaling pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL). Recurrent ...oncogenic mutations are found in the scaffold protein CARMA1 (CARD11) that connects B-cell receptor (BCR) signaling to the canonical NF-B pathway. We asked how far additional downstream processes are activated and contribute to the oncogenic potential of DLBCL-derived CARMA1 mutants. To this end, we expressed oncogenic CARMA1 in the NF-B negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identied recruitment of -catenin and its destruction complex consisting of APC, AXIN1, CK1 and GSK3 to oncogenic CARMA1. Recruitment of the -catenin destruction complex was independent of CARMA1-BCL10-MALT1 complex formation or constitutive NF-B activation and promoted the stabilization of -catenin. The -catenin destruction complex was also recruited to CARMA1 in ABC DLBCL cell lines, which coincided with elevated -catenin expression. In line, -catenin was frequently detected in non-GCB DLBCL biopsies that rely on chronic BCR signaling. Increased -catenin amounts alone were not sufcient to induce classical WNT target gene signatures, but could augment TCF/LEF-dependent transcriptional activation in response to WNT signaling. In conjunction with NF-B, -catenin enhanced expression of immunosuppressive interleukin-10 and suppressed antitumoral CCL3, indicating that -catenin can induce a favorable tumor microenvironment. Thus, parallel activation of NF-B and -catenin signaling by gain-of-function mutations in CARMA1 augments WNT stimulation and is required for regulating the expression of distinct NF-B target genes to trigger cell-intrinsic and extrinsic processes that promote DLBCL lymphomagenesis.
In human astrocytes, restriction of HIV replication involves inhibition of HIV Rev activity. We previously identified a Rev-interacting human protein fragment (16.4.1) that can reduce Rev activity. ...The 16.4.1 sequence is contained in a group of highly similar host cell proteins, which we call the Risp family. Here we investigate whether the Risp family is connected to HIV replication in astrocytes.
Cell/tissue lysates were analyzed for Risp expression by western blot with various anti-Risp antibodies. The interaction of astrocytic Risp members with Rev was investigated by affinity chromatography. Astrocytes were transfected with expression plasmids containing cDNAs encoding full-length Risp or the isolated 16.4.1 region for Risp overexpression or with siRNAs designed for Risp knock-down. Rev activity was investigated with a Rev-reporter assay. RNA levels were quantified by real-time RT-PCR, HIV Gag levels by p24ELISA.
Expression of the Risp family was demonstrated in human brain tissues and astrocytes. Astrocytes were shown to produce Risp family members that interact with Rev. Production of HIV Gag proteins and Rev-dependent RNAs in persistently infected astrocytes increased upon Risp knock-down and decreased upon Risp overexpression. Risp knock-down increased Rev activity and raised proportions of Rev proteins in the nucleus of astrocytes.
Our results link the Risp family to restriction of HIV production and inhibition of Rev activity in astrocytes. We conclude that the Risp family represents a novel family of host factors that can control HIV replication and may be important for the containment of HIV infection in brain reservoirs.
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