Tamoxifen is an estrogen analog and is the first example of a SERM. Tamoxifen shows estrogen-like agonist activity on bone and simultaneously displays estrogen antagonist activity on the breast. An unwanted effect of tamoxifen is its estrogen-like action on the uterus, what may increase the risk of endometrial carcinoma.
Transporter Associated with antigen Processing 1 (is induced by NF-kB). TAP belongs to the ABC family of ATP-dependent transporters. It transports peptides (which have been processed in the cytoplasm by the proteasome) into the ER, where the peptides are assembled into ternary complexes wit the alpha and beta2-m chains of the MHC1 for antigen presentation
Tat is one of the six known regulatory proteins of HIV-1. It is essential for HIV-1 replication, but it also might be involved in other nonimmune and immune dysfunctions during AIDS: Tat is secreted by infected cells and it induces angiogenesis and inflammation (thus contributing to Kaposi's carcinoma). Tat also induces apoptosis in T cells and inhibits T cell proliferation, and it induces the expression of a number of cytokines. Tat was reported to inhibit the killing of tumor targets by NK cells, apparently through blocking granzyme A secretion.
The TATA-binding protein (TBP) is one of the subunits of the transcription factor TFIID. TBP recognizes the TATA box and facilitates TFIID to bind to the promoter region of a gene. Once TFIID is bound to the promoter, other general transcription factors, along with RNA Pol II, assemble to the transcription complex.
T cell development
T cells develop within the thymus. Common lymphoid progenitors (that also give rise to B lymphocytes) leave the bone marrow and migrate to the thymus. There, the progenitor cells closely associate with the epithelial thymic stroma network by which a signal is transduced through the Notch1 receptor that commits the progenitors to the T cell lineage. Immature T cells are found within the thymic cortex, whereas more mature T cells are found within the medulla.
Immature progenitor cells that just enter the thymic cortex lack most of the surface molecules characteristic of mature T cells and their receptor genes are not yet rearranged. Interaction with the stroma results in a first signal that leads to the expression of T cell specific genes, such as CD2 and Thy-1 (in mice). But at this point they do not express the CD3:T-cell receptor complex nor the coreceptors CD4 or CD8. At this stage the cells are called double-negative thymocytes. These immature double-negative T cells correspond to about 60% of all thymocytes that lack CD4 and CD8. Another 20% of this double-negative pool are cells with rearranged gamma-delta T cell receptor and the remaining 20% display rearranged alpha-beta T cell receptors of very limited diversity but which in addition express the NK1.1 receptor (commonly found on NK cells) and which therefore are called NK T cells.
But back to the double-negative T cells with unrearranged T cell receptor: they give rise to the development of gamma-delta and alpha-beta T cells. In the alpha-beta pathway, the double negative thymocytes are distinguished by expression of adhesion molecules CD44, CD25, and Kit (the receptor of SCF). At first, the cells express Kit and CD44 but not CD25, and both chains of the T cell receptor are in the germline configuration. Then expression of CD25 is induced which later results in a decrease of Kit and CD44. Within those CD44low CD25+ thymocytes, rearrangement of the T cell receptor beta-chain locus occurs. If rearrangement is not successful, the cells remain in CD44low CD25+ and they eventually die, whereas cells with rearranged beta-chain lose expression of CD25 again. The rearranged beta-chains pair with a surrogate pre-T cell receptor alpha chain called pT-alpha, resulting in the formation of a pre-T-cell receptor which is expressed on the cell surface together with the CD3 molecules. The pre-T-cell receptor complex leads to proliferation, arrest of further beta-chain gene rearrangements, and expression of both, CD4 and CD8. Those double-positive thymocytes represent the vast majority of thymocytes. When the large double-positive thymocytes cease to proliferate, they become small double-positive cells which rearrange their alpha-chain locus. First, the small double-positive thymocytes express low levels of the T cell receptor and those that cannot recognize selfpeptide:self-MHC complexes fail positive selection and die. Those that pass positive selection increase expression of the T cell receptor and make the decision for being either CD4+ or CD8+ single positive cells. Thymocytes also undergo negative selection which eliminates those cells that recognize self-antigens. Only about 2% of all double-positive thymocytes survive this dual screening and mature as single-positive T cells.
Members of the Transforming Growth Factor beta family are cytokines that regulate the proliferation of cells; often they inhibit the cellular proliferation of normal cells.
T helper cells
CD4+ T cells can be divided into different subsets that drive distinct types of immune responses: T helper 1 (TH1) cells produce interferon-gamma (IFN-gamma) and TNF-alpha and via interaction with dendritic cells mainly activate cell-mediated immune responses. T helper 2 (TH2) cells produce interleukin 4 (IL-4), IL-5, IL-10 and IL-13 and via interaction with B cells mainly drive antibody-mediated responses. TH17 cells are another subset of T helper cells that produce IL-17, IL-6 and TNF-alpha and are centrally involved in mediating so called delayed-type hypersensitivity (DTH) reactions that cause tissue damage in conditions such as experimental autoimmune encephalomyelitis (EAE) (a model for multiple sclerosis) and rheumatoid arthritis. The differentiation of Th1, TH2 and TH17 cells is dependent on the action of distinct cytokines: IL-12 drives TH1 cells, IL4 drives TH2 cells and IL-23 drives TH17 cells. Interestingly, in a reciprocal fashion, the TH1 cytokine IFN-gamma suppresses TH2 differentiation, the TH2 cytokine IL-4 suppresses TH1 differentiation, and IFN-gamma plus IL-4 suppresses TH17 differentiation.
Therapeutic antibodies are monoclonal antibodies that specifically bind cellular target molecules and thereby inactivate the antigenic target or stimulate the destruction of a cell that carries the antigen. Thereby, therapeutic antibodies can be effective in destroying tumor cells: Trastuzumab (Herceptin) targets the receptor tyrosin kinase ErbB2 on breast cancer cells and Rituximab targets the CD20 marker molecule on B lymphocytes in lymphoma diseases. Therapeutic antibodies are also used in autoimmune conditions, such as Infliximab (Remicade) which inhibits TNF-alpha signaling.
Tumor Necrosis Factor Receptor family is important in mediating inflammation and cytotoxicity. Members of the TNFR family are the Death Receptors on the cell surface which mediate apoptosis upon stimulation by specific ligands. More.
Toll / IL-1R homology domain, an interleukin-1 receptor type 1-like intracellular signalling domain found in Toll receptors.
TNF receptor family
Death receptors belong to the tumor necrosis factor (TNF) receptor gene superfamily, which is defined by similar, cysteine-rich extracellular domains. In addition, the death receptors contain a homologous cytoplasmic sequence termed the "death domain". Death domains typically enable death receptors to engage the cell's apoptotic machinery, but in some instances they mediate functions that are distinct from or even counteract apoptosis. More...about TNF receptor mediated apoptosis.
TNFR1 is a prominent member of the tumor necrosis factor (TNF) receptor family, which upon activation by its ligand TNF-alpha can induce apoptosis in various cell types. Ligation by TNF-alpha leads to trimerization of TNFR1 and the association of the receptors' death domains. Subsequently, an adapter termed TRADD (TNFR-associated death domain) binds through its own death domain to the clustered receptor death domains. TRADD functions as an adapter that recruits several signaling molecules to the activated receptor: TNFR-associated factor-2 (TRAF2) and receptor-interacting protein (RIP) stimulate pathways leading to activation of NF-kB and of JNK/AP-1, whereas FADD mediates activation of apoptosis. More...
Toll-like receptor 2 (TLR2) is a Death Receptor without DD! TLR2 is a receptor of cells of the innate immune system activated by bacterial lipoproteins. Upon ligation, TLR2 recruits the adaptor molecule Myeloid Differentiation Factor 88 (MyD88) which binds to FADD and activates caspase-8 (Antonios et al., 2000, 19(13):3325-36).
Toll is a gene initially identified by the Nüsslein-Vollhard in Drosophila to be involved in insect immunity and early development. Toll is a type 1 transmembrane protein with extracellular domain rich in leucine repeats and a cytoplasmic domain with homology to the human IL-1 receptor. Flies with the Toll mutation proved to have severe defects in the production of antimicrobial peptides. The ligand for Toll is spaetzle.
Toll-like receptors (TLRs)
TLRs comprise a family of 11 members of innate immune receptors:
TLR1 is expressed ubiquitously and binds soluble bacterial factors and Tri-acyl peptides
TLR2 is expressed on the surface and in phagolysosomes of myeloid cells, mast cells, NK cells as well by mDCs and T cells. TLR2 binds bacterial lipoproteins, PGN, LTA, LPS as well as fungal zymosan, viral and parasitic antigens.
TLR3 is expressed intracellularly by mDCs and NK cells and detects dsRNA, siRNA, shRNA and endogeneous mRNA.
TLR4 is present on the surface of monocytes, mast cells, neutrophils as well as on T regs and gamma-delta T cells and endothelial cells. TLR4 recognizes bacterial LPS, viral proteins and endogeneous proteins such as HSP70, HSP90, fibronectin, fibrinogen...
TLR5 is found on the surface of epithelial and NK cells and mDCs monocytes and binds bacterial flagellin.
TLR6 is expressed on the surface of myeloid, mast, and B cells and forms heterodimers with TLR2.
TLR7 is found endosomal in pDCs, in B cells and endophils, binding viral ssRNA.
TLR8 is found endosomal in NK, T and myeloid cells and binds viral ssRNA.
TLR9 is expressed endosomal by pDCs, B/NK cells, and the surface of tonsillar cells. TLR9 binds bacterial and viral ssDNA.
TLR10 is found in B cells and pDCs, its ligand is not yet defined.
TLR11 was identified in mouse uroepithelium and identifies a profilin-like protein of the intracellular protozoan parasite Toxoplasma gondii (Hopkins and Sriskandan, 2005; Clin. Exp. Immunol., 140: 395-407), Lauw et al., 2005, Tr. Immunol., 26(10):509-511).
TP53 target gene 1 (TP53TG1) was identified in a differential display screen using a p53-inducible cell line. TP53TG1 was found to be induced in a p53-dependent manner following cellular stress such as exposure to UV, bleomycin or cis-platin (Takei et al., 1998, Genes Chr. Cancer, 23:1-9).
TPL-2 kinase is homologous to NIK. TPL-2 interacts with the C-terminus of NF-kB p105 and mediates phosphorylation of NF-kB p105 (probably not directly but by a downstream kinase). Upon phosphorylation, NF-kB p105 is either totally degraded or only partially degraded from its C-terminus by the proteasome to yield the NF-kB p50 subunit; while the p105 levels are clearly decreased by TPL-2 activity, the p50 levels remain quite constant. The degradation of p105 presumably generates active NF-kB by releasing associated NF-kB/Rel subunits from p105 which can translocate into the nucleus (Belich et al, 1999, Nature, 397: 363-368).
TNFR-Associated Death Domain (TRADD) is an adaptor molecule involved in TNFR1-mediated apoptosis pathways. More...
The process of transformation can be defined as "the introduction of inheritable changes in a cell causing changes in the growth phenotype and immortalization. Depending on the type and differentiation state of the corresponding cell, transformation is manifest in a number of ways, including morphological changes, increased saturation density, loss of contact inhibition, ability to grow in an anchorage-dependent manner or in multiple layers, reduced growth factor requirement in vitro, and an ability to form tumors upon inoculation into immunodefective hosts. The accumulation of several transforming events can increase the lifespan of the cell in vitro, occasionally leading to escape from senescence and the acquisition of unlimited proliferative capacity, commonly referred to as immortalization.
At some point, tumor cells must switch to an angiogenic phenotype in order to satisfy the necessary supply with nutrients for further growth of the tumor. This switch was found to coincide with loss of the wild-type allele of p53 and to be the result of reduced expression of thrombospondin-1 (TSP-1), a potent inhibitor of angiogenesis, in cultured fibroblasts from patients with Li-Fraumeni syndrome (Dameron et al., 1994, Science, 265: 1582-4).
Tumor suppressor proteins protect cells from uncontrolled proliferation and transformation into tumor cells. They affect several cellular pathways, such as those controlling proliferation, apoptosis, differentiation and genomic identity. The common definition of a tumor suppressor gene requires the demonstration of mutations of both copies of a candidate gene in tumors (Knudson's two-mutation criterion).
Terminal deoxyNucleotidyl (dUTP) transferase-mediated End Labeling. In vivo apoptose assay for the detection of DNA fragmentation in cells.
Type I and type II transmembrane proteins
Transmembrane proteins with their C-terminus residing within the cytoplasm are type I transmembrane proteins whereas those with their N-terminus exposed to the cytoplasm are type II transmembrane proteins.
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