Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The accumulation of G1 cell cycle-related proteins by resting or cycling B cells stimulated with B cell antigen receptor (BCR)- and T helper (Th) cell-derived signals is documented. Resting B cells constitutively express cyclin dependent kinase (cdk)4, cdk2 and the cyclin dependent kinase inhibitor (CKI), p27. The initiation of optimal proliferation with F(ab')2 anti-mu plus paraformaldehyde-fixed CD40 ligand-baculovirus-infected Sf9 cells (CD40L/Sf9 cells) increases accumulation of both cdk4 and cdk2 while decreasing p27 levels. B cells express cyclin D2 early during cycle progression, while cyclin D3 and E are not expressed until 18 h poststimulation and cyclin A by 24 h poststimulation. Cycling B cells express heightened levels of all these cyclins and cdks. Although neither BCR- nor CD40-mediated signals appreciably alter cycling B cell accumulation of cyclins D2, cdk4 and cdk2, the absence of BCR-derived signals results in a decreased accumulation of cyclins D3 and E. Finally, CD40-mediated signals induce resting B cells to accumulate the CKI, p21, while cycling B cells require both BCR- and CD40-mediated signals to maintain increased expression of p21. Thus, a Th cell-derived signal may impact upon both resting and cycling B cell cycle progression, at least in part, by regulating the accumulation of p21. The functional consequences of p21 accumulation as cells enter and move through the cell cycle are discussed.
Mol Immunol 1998 Jul
PMID:CD40-mediated induction of p21 accumulation in resting and cycling B cells. 982 56

By releasing interleukin (IL)-12 in the lung, alveolar macrophages (AM) may profoundly modify an immune response. The autocrine regulation of the heterodimeric, biologically active form of IL-12 (IL-12 p70) by IL-10 was studied, as well as the expression of its subunits of 35 kD (p35) and 40 kD (p40). AM cultured in medium alone expressed only p35 mRNA. Both p35 and p40 mRNA levels were induced by lipopolysaccharide (LPS) and were further increased by interferon-gamma (IFN-gamma). LPS alone induced IL-12 p40 but not IL-12 p70 production in monocytes and in AM. However, IL-12 p70 was released when the autocrine production of IL-10 was neutralized by IL-10 blocking antibody, and IL-12 p40 production increased. Although IFN-gamma markedly decreased LPS-induced IL-10 production in AM, neutralizing IL-10 further enhanced the level of LPS and IFN-gamma-induced IL-12 p70 in AM. In contrast, neutralizing the trace amount of IL-10 released by AM stimulated by CD40 crosslinking and IFN-gamma did not increase IL-12 p70. Thus, IL-12 p70 production by AM appears to be tightly controlled by the autocrine release of IL-10 when stimulated by LPS, or by LPS and IFN-gamma, whereas CD40 crosslinking triggered IL-12 p70 production in the absence of autocrine regulation by IL-10.
Am J Respir Cell Mol Biol 1999 Feb
PMID:Interleukin-12 production by human alveolar macrophages is controlled by the autocrine production of interleukin-10. 992 18

Cell-to-cell signals between T lymphocytes and antigen-presenting cells strictly regulate the development of the immune response. It has clearly emerged that among these signals few cell surface receptor-ligand pairs, such as CD40 and its ligand, CD154, are mandatory for the induction of lymphocyte activation. The early observation that mutations of CD154 gene are responsible for a human severe immunodeficiency primed an impressive number of studies aimed to functionally characterize this receptorial system in view of therapeutically exploiting its properties. Indeed, various approaches aimed to disrupt natural CD40-CD154 interaction were highly effective in the prevention and treatment of several experimental models of autoimmune disease and transplant rejection. In parallel, abnormalities of this pathway were constantly found in several immunologically-mediated human diseases. Furthermore, a number of studies have dissected the role of CD40 and its ligand in the immune response against various microbial and viral pathogens. Since these molecules are often expressed by tumor cells, it is not surprising that great efforts have been made to address their function also in the development of cancer. Most recent data strongly suggest an involvement of endothelial CD40 in the vascular processes that lead to atherogenesis. This review focuses on the most significant advances in the understanding of the molecular regulatory events involving CD40 and its ligand in experimental and human disease.
Int J Mol Med 1999 Apr
PMID:CD40-CD154 interaction in experimental and human disease (review). 1008 5

Human TRAF-3 is a signaling molecule that interacts with the cytoplasmic tails of CD40 and other TNF-receptor family members. TRAF-3 mRNA is expressed as two major classes of approximately 2 and 8 kb and a number of TRAF-3 encoding cDNA clones differ in discrete gene segments. Because this variety of mRNA species could result from mRNA processing events and/or multiple genes, the structure and localization of TRAF-3 encoding gene elements were determined. FISH and radiation hybrid mapping demonstrated that TRAF-3 is located at chromosome 14q32.3, approximately 1 Mb centromeric to the Ig heavy chain gene complex. Physical mapping of four overlapping genomic PAC clones established that TRAF-3 transcripts are encoded by a single gene, comprised of 13 exons and spanning 130 kb. Alternative polyadenylation in the mRNA segment encoded by exon 12 accounts for the difference between the 2 kb and the 8 kb classes of transcripts. Alternative mRNA splicing in the coding region (encoded by exons 3-12) generates transcripts which delete exons 8 (75 nt), 7+8 (156 nt) or 8+9 (168 nt) and that encode distinct protein isoforms (delta25, delta52 and delta56 aa, respectively). Alternative splicing of exon 2 (139 nt) and alternative transcriptional initiation result in mRNA species with distinct 5'UTRs. Together, these data indicate that a single TRAF-3 gene encodes a variety of mRNA species by a combination of alternative polyadenylation, alternative mRNA splicing and/or alternative initiation.
Mol Immunol 1998 Dec
PMID:A single gene for human TRAF-3 at chromosome 14q32.3 encodes a variety of mRNA species by alternative polyadenylation, mRNA splicing and transcription initiation. 1019 93

Transcription of germline Ig constant region genes and associated switch regions is an early and essential step in heavy chain class switch recombination. Transcription of the germline Cgamma1 and C epsilon Ig genes is induced by IL-4 via STAT6 activation; CD40 signaling can independently induce transcription of these genes and act in synergy with IL-4 to increase expression. In the present study, we investigated the role of three tandem NF-kappaB sites (site 1, -95; site 2, -71; site 3, -53) in the regulation of the germline Cgamma1 Ig promoter by CD40 Ligand (CD40L) and IL-4 in the mouse B lymphoma cell line, BCL1-3B3. Germline gamma1 transcripts are induced by CD40L and by IL-4 in BCL1-3B3 and the combination of signals is synergistic, as in normal B cells. EMSA with crude nuclear extracts demonstrated that stimulation with CD40L results in the induction of NF-kappaB complexes that bind to each of the three NF-kappaB sites and are composed mainly of p50 and RelB, but also include c-Rel and p65. Surprisingly, site-specific mutagenesis of the NF-kappaB sites did not reduce CD40-responsiveness of germline gamma1 promoter-luciferase reporter constructs transiently transfected into BCL1-3B3. Mutation in any one NF-kappaB site, however, significantly reduced overall transcriptional activity of the promoter, both basal and induced, suggesting a role in basal promoter function. In addition, activation of the promoter by IL-4 was blocked by mutation of all three NF-kappaB sites and similarly reduced by mutation of site 1, suggesting that NF-kappaB-STAT6 interactions may be necessary for STAT6-mediated transactivation of the germline gamma1 promoter. The results suggest that the three NF-kappaB sites may serve as a focus for formation of a higher-order transcription complex including STAT6, NF-kappaB and components of the basal transcription apparatus.
Mol Immunol 1999 Jan
PMID:Regulation of the germline immunoglobulin Cgamma1 promoter by CD40 ligand and IL-4: dual role for tandem NF-kappaB binding sites. 1036 18

CD40, a cell surface molecule found on B lymphocytes and other antigen presenting cells, can, when engaged by CD40 ligand (CD40L), induce gene rearrangements and isotype switching. We report here that CD40 is also expressed on thymocytes and on up to 50% of peripheral T cells from autoimmune prone strains of mice. In normal animals, CD40 is present on a small population of T cells and thymocytes. CD40 is expressed on most T cell hybridomas. We demonstrate that CD40 engagement on peripheral T cells, T cell hybridomas and thymocytes results in altered TCRValpha expression. That induced expression of different Valpha's results from the activity of the recombinase gene is implied by the observation that CD40 does not induce TCR changes in RAG knock-out mice. Total cell numbers remained unchanged between anti-CD40 treated and untreated populations of thymocytes or T cells indicating that treatment does not induce cell proliferation or cell death. The data presented here suggest a mechanism by which self reactive T cells accumulate peripherally and independently of selective processes of the thymus.
Int J Mol Med 1999 Sep
PMID:Increased expression of CD40 on thymocytes and peripheral T cells in autoimmunity: a mechanism for acquiring changes in the peripheral T cell receptor repertoire. 1042 71

Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are mediators of many members of the TNF receptor superfamily and can activate both the nuclear factor kappaB (NF-kappaB) and stress-activated protein kinase (SAPK; also known as c-Jun N-terminal kinase) signal transduction pathways. We previously described the involvement of a TRAF-interacting molecule, TRAF-associated NF-kappaB activator (TANK), in TRAF2-mediated NF-kappaB activation. Here we show that TANK synergized with TRAF2, TRAF5, and TRAF6 but not with TRAF3 in SAPK activation. TRAF2 and TANK individually formed weak interactions with germinal center kinase (GCK)-related kinase (GCKR). However, when coexpressed, they formed a strong complex with GCKR, thereby providing a potential mechanism for TRAF and TANK synergy in GCKR-mediated SAPK activation, which is important in TNF family receptor signaling. Our results also suggest that TANK can form potential intermolecular as well as intramolecular interactions between its amino terminus and carboxyl terminus. This study suggests that TANK is a regulatory molecule controlling the threshold of NF-kappaB and SAPK activities in response to activation of TNF receptors. In addition, CD40 activated endogenous GCKR in primary B cells, implicating GCK family proteins in CD40-mediated B-cell functions.
Mol Cell Biol 1999 Oct
PMID:TANK potentiates tumor necrosis factor receptor-associated factor-mediated c-Jun N-terminal kinase/stress-activated protein kinase activation through the germinal center kinase pathway. 1049 Jun 5

We have cloned, characterized and sequenced the murine TNF Receptor Associated Factor 1 (TRAF1) gene. Restriction mapping and Southern blotting analysis revealed that the TRAF1 gene comprises 10 exons and 9 intervening introns and spreads over 18 kb of genomic DNA. 5'-RACE analysis of the TRAF1 transcript using mRNA from activated spleen B cells revealed several transcription start sites between positions -42 to +4 relative to the 5'end of the murine TRAF1 cDNA sequence. We also isolated and sequenced the 5'-upstream promoter region, which lacks TATA-like and CAAT-like sites but contains GC-rich sequences. Taken together, these results suggest that the TRAF1 gene promoter is a member of the class of Sp-1-dependent promoters. Near the transcription initiation start site we identified three identical decanucleotide repeats (CCAGCCCAGC) which may play a role in the transcriptional regulation of TRAF1 expression. In addition we show that TRAF1 mRNA is not expressed in non-stimulated lymphocytes but can be induced upon activation with different stimuli, including anti-CD3, anti-IgM, anti-CD40 antibodies, LPS, or a combination of phorbol-12-myristate-13-acetate and ionomycin.
Mol Immunol 1999 Jun
PMID:Structure of the murine TRAF1 gene. 1049 14

Many members of the tumor necrosis factor receptor (TNFR) superfamily initiate intracellular signaling by recruiting TNFR-associated factors (TRAFs) through their cytoplasmic tails. TRAFs apparently recognize highly diverse receptor sequences. Crystal structures of the TRAF domain of human TRAF2 in complex with peptides from the TNFR family members CD40, CD30, Ox40, 4-1BB, and the EBV oncoprotein LMP1 revealed a conserved binding mode. A major TRAF2-binding consensus sequence, (P/S/A/T)x(Q/E)E, and a minor consensus motif, PxQxxD, can be defined from the structural analysis, which encompass all known TRAF2-binding sequences. The structural information provides a template for the further dissection of receptor binding specificity of TRAF2 and for the understanding of the complexity of TRAF-mediated signal transduction.
Mol Cell 1999 Sep
PMID:The structural basis for the recognition of diverse receptor sequences by TRAF2. 1051 13

Dendritic cells (DC) can be present at distinct stages of differentiation within the immune system. Sallusto and colleagues have recently described an in vitro culture system suitable for analyzing the maturation processes of DC (Sallusto and colleagues, J. Exp. Med. 1994;179:1109-1118). Monocytes cultured for 6 d in the presence of granulocyte macrophage colony-stimulating factor and interleukin-4 develop into immature DC with a high endocytic capacity but a low capacity to stimulate T cells. When challenged by lipopolysaccharide, these cells upregulate costimulatory molecules, express CD83, and become mature DC. CCR1 and CCR5 chemokine receptors are highly expressed on immature DC and downregulated on mature DC. This in vitro system was used to characterize human lung DC. Lung DC were shown to express some characteristics of in vitro immature DC. These are: (1) low expression of the costimulatory molecules CD40, CD80, and CD86; (2) poor expression of the differentiation marker CD83 and no CD1a; and (3) good capacity to incorporate dextran. Lung DC express moderate levels of CCR1 and CCR5. However, lung DC, like in vitro mature DC, express high levels of major histocompatibility complex Class II molecules, show low expression of CD14 and CD64, and are characterized by their high capacity to stimulate allogeneic T cells to proliferate during mixed leukocyte reactions (MLRs). Although lung DC express low levels of CD80 and CD86, the important role of these costimulatory molecules in inducing high MLR was demonstrated by using blocking antibodies. Therefore, while lung DC have overall a phenotype and an endocytic capacity close to in vitro immature DC, they share, like in vitro mature DC, a powerful capacity to stimulate T cells.
Am J Respir Cell Mol Biol 1999 Nov
PMID:Human lung dendritic cells have an immature phenotype with efficient mannose receptors. 1053 11


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