Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “tertiary lymphoid structures”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 199 records · Page 11Linked to original sources
PubMed2002

Genetic requirements for the episomal maintenance of oncogenic herpesvirus genomes.

Herpesviruses are large double-stranded DNA viruses that are characterized by lifelong latency. Epstein-Barr virus (EBV), the recently discovered Kaposi's sarcoma associated herpesvirus (KSHV), also referred to as human herpesvirus-8 (HHV-8), and the simian Herpesvirus saimiri (HVS) are associated with malignant lymphoproliferative diseases. These viruses establish latent infection in lymphoid cells. During latency only a few viral genes are expressed and the viral genome persists as a multicopy circular episome. The episome contains repetitive sequences that serve as multiple cooperative binding sites for the viral DNA binding proteins Epstein-Barr virus nuclear antigen 1 (EBNA-1) of EBV and latency-associated nuclear antigen (LANA1) of KSHV and HVS, which are expressed during latency. The oligomerized proteins associate with the viral genome and tether it to host chromosomes, assuring continual lifelong persistence of the virus.

Antigens, Viral↗
PubMed2000

Lineage specificity of CBFA2 fusion transcripts.

The CBFA2 gene on chromosome band 21q22 is one of the most commonly translocated genes in leukemia. As with other translocations, those involving CBFA2 are associated with specific disease phenotypes. Only one of the different translocations involving CBFA2, the t(12;21), has been associated with a non-myeloid lineage. Several different CBFA2 fusion transcripts were expressed in the myeloid 32Dcl3 cell line, and show that unlike the myeloid specific fusion transcripts, the lymphoid specific ETV6/CBFA2 transcript is not compatible with myeloid cell differentiation. It is shown that myeloid cells expressing the ETV6/CBFA2 transcript undergo apoptosis in response to a G-CSF differentiation signal. The molecular differences in the cells we studied are characterized using Western blot analysis to show that t(12;21) expressing cells fail to express the G-CSF receptor.

Acute Disease↗
PubMed1997

CD4: a co-receptor in the immune response and HIV infection.

CD4 is a transmembrane glycoprotein of the immunoglobulin superfamily, expressed on developing thymocytes, major histocompatibility class II (class II MHC) restricted mature T lymphocytes and, in humans, on cells of the macrophage/monocyte lineage. On lymphoid cells, CD4 plays a critical role during thymocyte ontogeny and in the function of mature T cells. CD4 binds to non-polymorphic regions of class II MHC acting as a co-receptor for the T-cell antigen receptor (TCR). It increases avidity between thymocytes and antigen-presenting cells and contributes directly to signal transduction through association with the Src-like protein tyrosine kinase p56lck. Its precise role on monocytes and macrophages is unclear. CD4 is also a co-receptor for the human and simian immunodeficiency viruses (HIV-1, HIV-2 and SIV). Clinically, CD4 antibodies may be used to achieve immunological tolerance to grafts and transplants.

Animals↗
PubMed2005

Combined loss of proapoptotic genes Bak or Bax with Bim synergizes to cause defects in hematopoiesis and in thymocyte apoptosis.

The proapoptotic members of the Bcl-2 family can be subdivided into members that contain several Bcl-2 homology (BH) domains and those that contain only the BH3 domain. Although it is known that BH3-only proteins and the multi-BH domain proteins, Bak and Bax, are essential for programmed cell death, the overlapping role of these two subgroups has not been examined in vivo. To investigate this, we generated Bak/Bim and Bax/Bim double deficient mice. We found that although Bax-/-Bim-/-, but not Bak-/-Bim-/-, mice display webbed hind and front paws and malocclusion of the incisors, both groups of mice present with dysregulated hematopoiesis. Combined loss of Bak and Bim or Bax and Bim causes defects in myeloid and B-lymphoid development that are more severe than those found in the single knock-out mice. Bak-/-Bim-/- mice have a complement of thymocytes that resembles those in control mice, whereas Bax-/-Bim-/- mice are more similar to Bim-/- mice. However, thymocytes isolated from Bak-/-Bim-/- or Bax-/-Bim-/- mice are markedly more resistant to apoptotic stimuli mediated by the intrinsic pathway as compared with thymocytes from single-knockout mice. These data suggest an essential overlapping role for Bak or Bax and Bim in the intrinsic apoptotic pathway.

Abnormalities, Multiple↗
PubMed2001

Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor-ligand specificity.

RANK, the receptor activator of NF-kappaB, and its ligand RANKL (initially termed TRANCE, also termed ODF and OPGL), are a TNF superfamily receptor-ligand pair that govern the development and function of osteoclasts, lymphoid tissue, and mammary epithelium. While TNF family cytokines share a common structural scaffold, individual receptor-ligand pairs associate with high specificity. Given the low level of amino acid conservation among members of the TNF superfamily, the means by which these molecules achieve specificity cannot be completely understood without knowledge of their three-dimensional structures. To determine the elements of RANKL that mediate RANK activation, we have crystallized the ectodomain of murine RANKL and solved its structure to a resolution of 2.6 A. RANKL self-associates as a homotrimer with four unique surface loops that distinguish it from other TNF family cytokines. Mutagenesis of selected residues in these loops significantly modulates RANK activation, as evidenced by in vitro osteoclastogenesis, thereby establishing their necessity in mediating the biological activities of RANKL. Such structural determinants of RANKL-RANK specificity may be of relevance in the pharmacologic design of compounds to ameliorate osteopenic disorders of bone.

Animals↗
PubMed2004

A direct binding site for Grb2 contributes to transformation and leukemogenesis by the Tel-Abl (ETV6-Abl) tyrosine kinase.

A direct binding site for the Grb2 adapter protein is required for the induction of fatal chronic myeloid leukemia (CML)-like disease in mice by Bcr-Abl. Here, we demonstrate direct binding of Grb2 to the Tel-Abl (ETV6-Abl) fusion protein, the product of complex (9;12) chromosomal translocations in human leukemia, via tyrosine 314 encoded by TEL exon 5. A Tel-Abl point mutant (Y314F) and a splice variant without TEL exon 5 sequences (Deltae5) lacked Grb2 interaction and exhibited decreased binding and phosphorylation of the scaffolding protein Gab2 and impaired activation of phosphatidylinositol 3-kinase, Akt, and extracellular signal-regulated kinase/mitogen-activated protein kinase in hematopoietic cells. Tel-Abl Y314F and Deltae5 were unable to transform fibroblasts to anchorage-independent growth and were defective for B-lymphoid transformation in vitro and lymphoid leukemogenesis in vivo. Previously, we demonstrated that full-length Tel-Abl induced two distinct myeloproliferative diseases in mice: CML-like leukemia similar to that induced by Bcr-Abl and a novel syndrome of small-bowel myeloid infiltration endotoxemia and hepatic and renal failure. Lack of the Grb2 binding site had no effect on development of small bowel syndrome but significantly attenuated the induction of CML-like disease by Tel-Abl. These results suggest that direct binding of Grb2 is a common mechanism contributing to leukemogenesis by oncogenic Abl fusion proteins.

Adaptor Proteins, Signal Transducing↗
PubMed1999

The GYF domain is a novel structural fold that is involved in lymphoid signaling through proline-rich sequences.

T cell activation through the CD2 cell surface receptor is transmitted by proline-rich sequences within its cytoplasmic tail. A membrane-proximal proline-rich tandem repeat, involved in cytokine production, is recognized by the intracellular CD2 binding protein CD2BP2. We solved the solution structure of the CD2 binding domain of CD2BP2, which we name the glycine-tyrosine-phenylalanine (GYF) domain. The GYF sequence is part of a structurally unique bulge-helix-bulge motif that constitutes the major binding site for the CD2 tail. A hydrophobic surface patch is created by motif residues that are highly conserved among a variety of proteins from diverse eukaryotic species. Thus, the architecture of the GYF domain may be widely used in protein-protein associations.

Adaptor Proteins, Signal Transducing↗
PubMed2006

The N-terminal domain of CCL21 reconstitutes high affinity binding, G protein activation, and chemotactic activity, to the C-terminal domain of CCL19.

CC chemokine receptor 7 (CCR7), which regulates the trafficking of leucocytes to the secondary lymphoid organs, has two endogenous chemokine ligands: CCL19 and CCL21. Although both ligands possess similar affinities for the receptor and similar abilities to promote G protein activation and chemotaxis, they share only 25% sequence identity. Here, we show that substituting N-terminal six amino acids of CCL21 (SDGGAQ) for the corresponding N-terminal domain of CCL19 (GTNDAE) results in a chimeric chemokine that exhibits high affinity binding and G protein activation of CCR7. These data demonstrate that despite dissimilar sequences, the amino terminal hexapeptide of these two chemokines is capable of performing similar roles resulting in receptor activation.

Amino Acid Sequence↗
PubMed2000

Two novel human and mouse DNA polymerases of the polX family.

We describe here two novel mouse and human DNA polymerases: one (pol lambda) has homology with DNA polymerase beta while the other one (pol mu) is closer to terminal deoxynucleotidyltransferase. However both have DNA polymerase activity in vitro and share similar structural organization, including a BRCT domain, helix-loop-helix DNA-binding motifs and polymerase X domain. mRNA expression of pol lambda is highest in testis and fetal liver, while expression of pol mu is more lymphoid, with highest expression both in thymus and tonsillar B cells. An unusually large number of splice variants is observed for the pol mu gene, most of which affect the polymerase domain. Expression of mRNA of both polymerases is down-regulated upon treatment by DNA damaging agents (UV light, gamma-rays or H(2)O(2)). This suggests that their biological function may differ from DNA translesion synthesis, for which several DNA polymerase activities have been recently described. Possible functions are discussed.

Alternative Splicing↗
PubMed2005

The zinc finger transcription factor Growth factor independence 1 (Gfi1).

Growth Factor Independence 1 (Gfi1) is a transcriptional repressor with a molecular weight between 47 and 55 kDa The protein has six C-terminal C2H2-type zinc-finger domains and a characteristic stretch of 20 amino acids, called the SNAG-domain, at its N-terminus. Expression of Gfi1 ranges from the hematopoietic and lymphoid system, to sensory epithelia, lung and parts of the CNS. Gene knock-out studies revealed that Gfi1 is essential for the development of granulocytes and plays a role in T-cell differentiation and macrophage-dependent cytokine production, indicating that this protein shares responsibility for different lines of defense against pathogens. Also, Gfi1 is required for the proper development of inner ear hair cells illustrated by ataxia and deafness in knock-out mice. While hereditary hearing loss has so far not been associated with Gfi1 malfunction, crippling mutations in the Gfi1 gene have been reported in patients suffering from neutropenia suggesting an important role of Gfi1 in this human disease.

Amino Acid Sequence↗
PubMed2006

Molecular cloning and characterization of Toll-like receptor 9 in Japanese flounder, Paralichthys olivaceus.

Toll-like receptor (TLR) 9 cDNA and gene were cloned from Japanese flounder, Paralichthys olivaceus. The Japanese flounder TLR9 cDNA encodes 1065 amino acids. The leucine-rich domain (LRD) and the Toll/interleukin-1 receptor (TIR) domain found in other vertebrate TLR9s were conserved in Japanese flounder TLR9. The gene is composed of three exons and two introns. The Japanese flounder tumor necrosis factor (TNF) gene promoter was activated in Japanese flounder TLR9-transformed hirame natural embryo (HINAE) cells upon stimulation with synthesized CpG oligodeoxynucleotide (ODN), but not by stimulation with GpC ODN. The Japanese flounder TLR9 gene was highly expressed in epithelial and lymphoid organs, such as the gills, intestines, kidney, spleen and stomach in an apparently healthy fish. The mRNA copy numbers of Japanese flounder TLR9 and its adapter protein, the myeloid differentiation factor 88 (MYD88) were increased in some organs including blood, gill, kidney and spleen after Edwardsiella tarda challenge. Immunohistochemical analysis revealed that TLR9 and MYD88 were expressed in the same cells of kidney. Few TLR9-expressing cells were found in gill, kidney and spleen in healthy Japanese flounder, but many were found in these organs after E. tarda challenge and were coincident with lesions that had been colonized by the bacteria.

Amino Acid Sequence↗
PubMed2004

Mutual functional destruction of HIV-1 Vpu and host TASK-1 channel.

Sequence analysis predicted significant structural homology between the HIV-1 accessory protein Vpu and the N-terminal region of TASK-1, a mammalian background K(+) channel. If the homology resulted from molecular piracy during HIV-1 evolution, these two proteins may have important functional interactions. Here we demonstrate that TASK and Vpu physically interact in cultured cells and in AIDS lymphoid tissues. The functional consequences were potentially destructive for both components: Vpu abolished TASK-1 current, while overexpressing TASK led to a marked impairment of Vpu's ability to enhance viral particle release. Further, the first 40 amino acids of TASK-1 (part of the homology to Vpu) were capable of enhancing HIV-1 particle release. This virus-host interaction may influence HIV-1/AIDS progression, as well as electrical signaling in infected host tissues.

Amino Acid Sequence↗
PubMed2004

Janus kinase 3: a novel target for selective transplant immunosupression.

Existing immunosuppressants inhibit lymphocyte activation and T cell cytokine signal transduction pathways, reducing the rate of acute rejection episodes to < 10%. However, the widespread tissue distribution of their molecular targets engenders pleiotropic toxicities. One strategy to address this problem seeks to identify compounds that selectively inhibit a target restricted in distribution to the lymphoid system. Janus kinase (Jak) 3 is such a molecule; it mediates signal transduction via the gamma common chain of lymphokine surface receptors. Disruption of this lymphoid-restricted enzyme would not be predicted to produce collateral damage in other organ systems. Development of selective Jak3 inhibitors has been difficult due to crossreactivity with its homologue, Jak2. In contrast to all other putative antagonists, which are discussed in detail herein, one Jak3 inhibitor, NC1153, shows at least 40-fold greater selective inhibition for Jak3 than for Jak2, is robustly synergistic with calcineurin antagonists, and, either alone or in combination with cyclosporin, produces no adverse effects in rodents preconditioned to be at heightened risk for nephrotoxicity, bone marrow suppression, or altered lipid metabolism.

Amino Acid Sequence↗
PubMed2000

Mouse models in the study of the Ets family of transcription factors.

The Ets family of transcription factors is one of a growing number of master regulators of development. This family was originally defined by the presence of a conserved DNA binding domain, the Ets domain. To date, nearly 30 members of this family have been identified and implicated in a wide range of physiological and pathological processes. Despite the likely importance of Ets-family members, each of their precise roles has not been delineated. Herein, we describe the elucidation of essential functions of a few of these family members in vivo using knockout mouse models. Of the knockouts generated to date, the majority shows important functions in hematopoiesis, ranging from PU.1, a principle regulator of myelo-lymphopoiesis, to Spi-B which regulates the proper function of terminally differentiated cells. Ets1 was shown to be of intermediate importance as a regulator of pan-lymphoid development. Other Ets family members such as Fli1 and TEL1 display distinct and/or overlapping functions in vasculo/angiogenesis, hemostasis and hematopoiesis. The remaining knockouts generated, Ets2 and Er81, show non-hematopoietic defects related to extraembryonic development and neurogenesis, respectively. The pioneering group of knockout models described reveals only the most distinct functions of each of these Ets family members. A better understanding of the roles and hierarchies of Ets family members in cellular differentiation will come with the generation of new null alleles in previously untargeted family members, more mutant alleles in members already disrupted, double knockouts, ES cell differentiation and chimera rescue experiments, and tissue-specific inducible knockouts.

Animals↗
PubMed2004

Physical and functional interaction of CARMA1 and CARMA3 with Ikappa kinase gamma-NFkappaB essential modulator.

CARMA proteins are scaffold molecules that contain a caspase recruitment domain and a membrane-associated guanylate kinase-like domain. CARMA1 plays a critical role in mediating activation of the NFkappaB transcription factor following antigen receptor stimulation of both B and T lymphocytes. However, the biochemical mechanism by which CARMA1 regulates activation of NFkappaB remains to be determined. Here we have shown that CARMA1 and CARMA3 physically associate with Ikappa kinase gamma/NFkappaB essential modulator (IkappaKgamma-NEMO) in lymphoid and non-lymphoid cells. CARMA1 participates to an inducible large molecular complex that contains IkappaKgamma/NEMO, Bcl10, and IkappaKalpha/beta kinases. Expression of the NEMO-binding region of CARMA3 exerts a dominant negative effect on Bcl10-mediated activation of NFkappaB. Thus, our results provide direct evidence for physical and functional interaction between CARMA and the IkappaK complex and offer a biochemical framework to understand the molecular activities controlled by CARMA-1, -2, and -3 and Bcl10.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Carma1, a CARD-containing binding partner of Bcl10, induces Bcl10 phosphorylation and NF-kappaB activation.

Bcl10, a caspase recruitment domain (CARD)-containing protein identified from a breakpoint in mucosa-associated lymphoid tissue (MALT) B lymphomas, is essential for antigen-receptor-mediated nuclear factor kappaB (NF-kappaB) activation in lymphocytes. We have identified a novel CARD-containing protein and interaction partner of Bcl10, named Carma1. Carma1 is predominantly expressed in lymphocytes and represents a new member of the membrane-associated guanylate kinase family. Carma1 binds Bcl10 via its CARD motif and induces translocation of Bcl10 from the cytoplasm into perinuclear structures. Moreover, expression of Carma1 induces phosphorylation of Bcl10 and activation of the transcription factor NF-kappaB. We propose that Carma1 is a crucial component of a novel Bcl10-dependent signaling pathway in T-cells that leads to the activation of NF-kappaB.

Amino Acid Sequence↗
PubMed2004

Frontline: Characterization of BT3 molecules belonging to the B7 family expressed on immune cells.

New members of the B7 family have been recently described as regulators of T cell activation and function. Butyrophilin (BT) has also been related to the B7 family by sequence similarity analyses. We present a new subfamily called BT3, which belongs to the B7/BT family. The BT3 subfamily comprises three members (BT3.1,.2 and.3) that exhibit 95% identity and form a monophylogenetic group along with the BT-related members. High expression levels of BT3 transcripts were detected in lymphoid tissues (mainly spleen, lymph node and PBL). Using anti-BT3 mAb we could demonstrate BT3 expression on immune cells including T, B and NK cells, monocytes and dendritic cells as well as hematopoietic precursors and some tumor cell lines. As described earlier for PDL-1 and ICOS-L, BT3 molecules are expressed on endothelial cells and up-regulated upon activation by IFN-gamma or TNF-alpha. The BT3.1 counter-receptor (BT3.1-R) was analyzed by means of binding experiments using BT3.1-Ig soluble protein. The BT3.1-R is not CD28, CTLA-4, ICOS, PD-1 or BTLA and seems restricted to some T cell and hematopoietic cell lines. Altogether, these data describe new members of the B7/BT family that may play a role in regulation of the immune response.

Amino Acid Sequence↗
PubMed2003

Bcl10 protein can act as a transcription activator in yeast.

The Bcl10 gene has recently been cloned from the chromosomal translocation t(1:14) (p22; q32) in a low-grade mucosa-associated lymphoid tissue (MALT) lymphoma, and was implicated in the pathogenesis of this and several other tumor types. In yeast two hybrid systems, when it was fused to Gal4 DNA-binding domain of pGBT9, this fusion protein can activate the expression of reporter genes without Gal4-AD domain. Through deletion assay and secondary structure prediction, we found that the N-terminal of Bcl10 contributed more to activation than the C-terminal. It has been recently reported that Bcl10 expression is correlated with the activation of NF-kappaB in eukaryotic cells, so it may represent an important role in protein expression. Our research is the first to demonstrate a new function of Bcl10: transcription activation in yeast.

Adaptor Proteins, Signal Transducing↗