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P100, which is encoded by NF-kappa B2, inhibits Rel dimers. It can also be processed into p52, one of the DNA binding sub-units of NF-kappa B/Rel factors. Several p100 C-terminal truncations that result from gene rearrangements are associated with lymphomagenesis. Here, we characterized a new p100 mutant that we termed p100HB. It originates from a point-mutation that generates a premature stop-codon, and thus the protein lacks the last 125 amino acids. We have detected p100HB in several human tumor cell lines. The truncated protein is mainly unprocessed, and although it still binds Rel dimers, it has reduced inhibitory potency compared to p100 and translocates into the nucleus. Thus, p100HB may be associated with deregulated NF-kappa B/Rel functions.

Tumor necrosis factor-α (TNF-α) and lymphotoxin-β receptor (LTβR) signaling both play important roles in inflammatory and immune responses through activation of NF-κB. Using various deficient mouse embryonic fibroblast cells, we have compared the signaling pathways leading to NF-κB induction in response to TNF-α and LTβR activation. We demonstrate that LTβR ligation induces not only RelA/p50 dimers but also RelB/p50 dimers, whereas TNF-α induces only RelA/p50 dimers. LTβR-induced binding of RelB/p50 requires processing of p100 that is mediated by IKKα but is independent of IKKβ, NEMO/IKKγ, and RelA. Moreover, we show that RelB, p50, and p100 can associate in the same complex and that TNF-α but not LTβ signaling increases the association of p100 with RelB/p50 dimers in the nucleus, leading to the specific inhibition of RelB DNA binding. These results suggest that the alternative NF-κB pathway based on p100 processing may account not only for the activation of RelB/p52 dimers but also for that of RelB/p50 dimers and that p100 regulates the binding activity of RelB/p50 dimers via at least two distinct mechanisms depending on the signaling pathway involved.

Tumor necrosis factor alpha (TNFalpha) is a potent proinflammatory cytokine that plays an important role in immunity and inflammation, and in the control of cell proliferation, differentiation and apoptosis. TNFalpha is also the founding member of a still growing family of cytokines with diverse bioregulatory functions. Considerable progress has been made in understanding the molecular mechanisms that mediate TNFalpha-induced cellular responses. Binding of TNFalpha to its two receptors, TNFR1 and TNFR2, results in recruitment of signal transducers that activate at least three distinct effectors. Through complex signaling cascades and networks, these effectors lead to the activation of caspases and two transcription factors, AP-1 and NF-kappaB. Similar signaling mechanisms are likely to be used by other members of the TNF family. This review focuses on proteins that transduce the signals generated at TNF receptors to nuclear targets such as AP-1 and NF-kappaB.

Proteins with seven transmembrane segments (7TM) define a superfamily of receptors (7TM receptors) sharing the same topology: an extracellular N-terminus, three extramembranous loops on either side of the plasma membrane, and a cytoplasmic C-terminal tail. Upon ligand binding, cytoplasmic portions of the activated receptor interact with heterotrimeric G-coupled proteins to induce various second messengers. A small group, recently recognized on the basis of homologous primary amino acid sequences, comprises receptors to hormones of the secretin/vasoactive intestinal peptide/glucagon family, parathyroid hormone and parathyroid hormone-related peptides, growth hormone-releasing factor, corticotropin-releasing factor, and calcitonin. A cDNA, extracted from a neuroectodermal cDNA library, was predicted to encode a new 886-amino-acid protein with three distinct domains. The C-terminal third contains the seven hydrophobic segments and characteristic residues that allow the protein to be readily aligned with the various hormone receptors in the family. Six egf-like modules, at the N-terminus of the predicted mature protein, are separated from the transmembrane segments by a serine/threonine-rich domain, a feature reminiscent of mucin-like, single-span, integral membrane glycoproteins with adhesive properties. Because of its unique characteristics, this putative egf module-containing, mucin-like hormone receptor has been named EMR1. Southern analysis of a panel of somatic cell hybrids and fluorescence in situ hybridization have assigned the EMR1 gene to human chromosome 19p13.3.

Introduction Les etudes physiopathologiques sur l’arterite a cellules geantes (ACG) ont porte, avant tout, sur le dysfonctionnement du systeme immunitaire. Les mecanismes qui conduisent au remodelage arteriel et a l’eventuelle occlusion des vaisseaux sont mal connus et le role des cellules musculaires lisses vasculaires (CMLV) dans ce contexte reste a identifier. Nous avons identifie que l’endotheline-1 interagissait avec de nombreuses proteines dont l’expression par les CMLV se modifie au cours de l’ACG. Materiels et methodes Nous avons etudie l’expression de l’endotheline-1 (ET-1) et de ses recepteurs ETAR et ETBR par qPCR a partir de CMLV isolees d’artere temporale de patients suspects d’ACG et avons etudie leur expression proteique par immuno-histochimie. Nous avons etudie la proliferation des CMLV de patients atteints d’ACG comparativement a des CMLV d’aorte normale (HAoSMC) en presence de bosentan, d’ambrisentan, de macitentan et de son metabolite actif mais egalement de sildenafil et d’iloprost. Resultats Nous avons pu confirmer par qPCR l’augmentation d’expression de l’ARN de l’ET-1 et de l’ETBR dans les CMLV de patients atteints d’ACG comparativement a des CMLV de patients temoins ( p p Conclusion Nous avons confirme l’implication de l’ET-1 et de ses recepteurs ETAR et ETBR au cours de l’ACG. L’inhibition de la proliferation excessive des CMLV de patients atteints d’ACG par le macitentan et en particulier par son metabolite actif ouvre la voie a un usage therapeutique de cette molecule.

Introduction Les etudes physiopathologiques sur l’arterite a cellules geantes (ACG) ont porte, avant tout, sur le dysfonctionnement du systeme immunitaire. Les mecanismes qui conduisent au remodelage arteriel et a l’eventuelle occlusion des vaisseaux sont mal connus et le role des cellules musculaires lisses vasculaires (CMLV) dans ce contexte reste a identifier. Materiels et methodes Nous avons cultive des CMLV issues d’artere temporale de patients suspects d’ACG. Nous avons retenus les CMLV de 4 patients avec ACG prouvee histologiquement (TAB ± ACG), de 4 patients avec ACG sans preuve histologique (TAB--ACG) et de 4 patients ayant un autre diagnostic que l’ACG (GCA-controls) et avons analyse les proteomes par 2D-DIGE a pH 3-11. Les CMLV d’aorte normale (HAoSMC) ont ete utilise comme controle. Par ailleurs, nous avons fait une analyse du profil d’expression genique a l’aide de puces Affymetrix®. Resultats Nous avons identifie que 16, 30 et 2 proteines de CMLV respectivement etaient differemment exprimees entre les groupes TAB ± GCA et GCA-control, entre les groupes TAB ± GCA et TAB–GCA et entre les groupes TAB–GCA et GCA-control (rapport d’expression ≥ 1,5 et p ≤ 0,05). Nous avons pu montrer que parmi les 153 proteines differemment exprimees entre les CMLV du groupe TAB + -GCA et HAoSMC, de nombreuses etaient liees a la paxilline. De nombreux genes parmi ceux differemment exprimes entre les groupes TAB ± GCA et GCA-control sont impliques dans la proliferation cellulaire. La paxilline a de nouveau ete identifiee comme lien entre les genes d’interet. Conclusion Le contenu proteique et le profil d’expression genomique des CMLV se modifie au cours de l’ACG. Cela pourrait temoigner d’une capacite de proliferation accrue de ces CMLV. La paxilline pourrait constituer une cible therapeutique qui pourrait permettre d’inhiber le remodelage vasculaire au cours de l’ACG.

FLI1 is a common mouse viral integration region in virus-induced leukemias and lymphomas. Using an evolutionarily conserved mouse probe and Southern hybridization to (rodent x human) somatic cell hybrid DNAs, the human homolog of FLI1 has been shown to lie on a fragment of chromosome 11 flanked on the centromeric side by the acute lymphoblastic leukemia-associated t(4;11)(q21;q23) translocation breakpoint and on the telomeric side by the Ewing- and neuroepithelioma-associated t(11;22) (q24;q12) breakpoint.