Members of the TNFR (Tumor Necrosis Factor Receptor) superfamily are important for cell growth and survival. CD27 is a member of the TNFR superfamily, which includes TNFR types I and II, NGFR (Nerve Growth Factor Receptor), CD30 (associated with Hodgkin lymphoma), Fas/Apo1 (CD95), CD40, 4–1BB, and OX40. These receptors are known to play a very important role in cell growth and differentiation, as well as apoptosis or programmed cell death. In addition to providing costimulatory signals for cell proliferation, ligation of both TNFR1 and Fas can result in programmed cell death or apoptosis. The underlying mechanism requires an intact 80-aa stretch present in the cytoplasmic tails of both TNFR1 and Fas, termed the DD (Death Domain) (Ref.1). CD27 is a disulfide-linked[..]

PKR (Protein Kinase-R) is a 68-kDa serine–threonine kinase that appears to play a primary role in mediating the antiviral activities of infected cells. PKR mediates apoptosis induced by many different stimuli, such as LPS (Lipopolysaccharides), TNF-Alpha (Tumour Necrosis Factor-Alpha), viral infection, or serum starvation. Viral infection leads to the increased expression and secretion of the cytokine IFN-Gamma (Interferon- Gamma) from host cells. IFN-gamma induces the dsRNA (Double-Stranded RNA)-dependent PKR. dsRNA, produced during viral replication, is an active component of a viral infection that stimulates antiviral responses in infected cells (Ref.1). The PKR protein is enzymatically inactive unless it is activated by binding to dsRNA. PKR activates as a kinase[..]

Phosphatase and tensin homolog deleted from chromosome 10 (PTEN) is a tumor suppressor protein, that is linked to AKT signaling, critically controlling proliferation, survival, migration, energy metabolism and cellular architecture in hematopoietic cells. PTEN is a dual-specificity protein phosphatase and an inositol phospholipid phosphatase that dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PIP3), thus producing phosphatidylinositol 4,5-bisphosphate (PIP2) and thereby negatively regulating oncogenic and nononcogenic PI3K/AKT signaling. PTEN may have additional phosphatase-independent activities, as well as other functions in the nucleus (Ref.1 and 2). PTEN's tumor-suppressing function largely relies on the protein's phosphatase activity and subsequent[..]

GITR (Glucocorticoid-Induced TNFR Family-Related) also termed AITR (Activation-Inducible TNFR Family Receptor) is a member of the TNFRSF18 (TNF Receptor Superfamily 18). It is a 228-amino acids type I transmembrane protein that is suggested to be a close relative of 4-1BB and CD27. Inducible during T-Cell activation, the molecule has a 19 amino acid residue signal sequence, a 134 amino acid residue extracellular region, a 23 amino acid residue transmembrane segment and a 52 amino acid residue cytoplasmic domain. It has three cysteine-rich motifs in its extracellular region. Its ligand is GITRL (AITRL). GITR expression is upregulated on T-Cells. A high level of GITR is constitutively expressed on CD4+ CD25+ regulatory T-Cells. CD4+ GITR+ T-Cells are equivalent to CD4+[..]

The TNFR (Tumor Necrosis Factor Receptor) superfamily comprises a growing family of type I membrane bound glycoproteins, which interact with the TNF family of soluble mediators and type II transmembrane proteins. At least 23 TNFR superfamily members and 17 known ligands have been identified in mammals. These receptors trigger pleiotropic responses, ranging from apoptosis and differentiation to proliferation, and have been implicated in immune regulation, host defense and lymphoid organ development. Members of the TNFR family are characterized by the presence of varying numbers (two to six) of cysteine-rich repeats in their cytoplasmic domains. Among these molecules, a novel subgroup has been defined, termed DR (Death Receptors), as one of their most prominent functions[..]

Tumor necrosis factor (TNF) is a pro-inflammatory cytokine with the capacity to induce apoptosis. It is enriched in the tumor microenvironment, promotes tumor growth and subverts innate immune responses to cancer cells. TNF is the best studied member of the TNF superfamily. TNF-alpha can bind to two related receptors, TNF receptors 1 and 2 (TNFR1 and TNFR2), which are also used by other, similar ligands. By binding to TNFR1 and TNFR2, TNF activates distinct signaling pathways important for cell proliferation, cell death and immune responses (Ref.1 and 2). TNFR1 is constitutively expressed in most cell types (Ref.3).The default effect of TNF stimulation is to activate the nuclear factor-kappaB (NF-kappaB) pathway and mediate inflammation. TNFR1 mediates the cytotoxic[..]

Tumor necrosis factor (TNF) is a pro-inflammatory cytokine with the capacity to induce apoptosis. It is enriched in the tumor microenvironment, promotes tumor growth and subverts innate immune responses to cancer cells. TNF is the best studied member of the TNF superfamily. TNF-alpha can bind to two related receptors, TNF receptors 1 and 2 (TNFR1 and TNFR2), which are also used by other, similar ligands. By binding to TNFR1 and TNFR2, TNF activates distinct signaling pathways important for cell proliferation, cell death and immune responses (Ref.1 and 2). TNFR2 is typically restricted to certain subpopulations of immune cells such as CD4+ or CD8+ T cells and a few other cell types such as oligodendrocytes and endothelial cells (Ref.3).TNFR2 signaling has significant[..]

UV radiation induces two of the most abundant mutagenic and cytotoxic DNA lesions such as  CPD  (Cyclobutane-Pyrimidine Dimers) or 6-4PPs (6-4 Pyrimidine Pyrimidone). The most common covalently linked adjoining pyrimidines are TT(Thymine dimers), T-C (Thymine-Cytosine dimers) and C-C (Cytosine-Cytosine dimers). T-T dimers cause kinks in the DNA strand that prevent both replication and transcription of that part of the DNA. Because they block DNA replication (and therefore prevent cells from reproducing), T-T dimers and other forms of UV damage cannot be inherited, and thus do not constitute mutations. Such kinds of DNA damage are known as premutational lesions because they prevent both transcription and replication of the genes in which they are present and[..]

BMPs (Bone morphogenetic proteins) are the members of the transforming growth factor-beta superfamily of secreted signaling molecules [Ref.1]. Transduction of BMP signal involves two types of transmembrane serine/threonine kinase receptors: type I and type II [Ref.1]. BMP2, BMP4, BMP5,BMP6, BMP7, BMP8, BMP9, BMP10, BMP12, BMP13 and BMP14 (Bone morphogenetic protein 2, 4, 5, 6 ,7, 8, 9, 10, 12, 13 and 14) can bind to three type I receptors: BMPR1A (Bone morphogenetic protein receptor, type IA), BMPR1B (Bone morphogenetic protein receptor, type IB) and ALK-2 (Activin A receptor, type I) and two type II receptor, BMPR2A (Bone morphogenetic protein receptor type IIA) and ACTRIIA [Ref.1]. Various antagonists such as, Noggin, Tsg (twisted gastrulation), GREM1, Follistatin[..]

PKC (Protein Kinase-C) is a cyclic nucleotide-independent enzyme that phosphorylates serine and threonine residues in many target proteins. PKC plays a pivotal role in mediating cellular responses to extracellular stimuli involved in proliferation, differentiation, apoptosis, and exocytotic release in a number of non-neuronal systems such as Islet cells, Chromaffin cells and Paramecium. PKC has also been implicated in phosphorylation of several neuronal proteins, which are thought to regulate neurotransmitter release and establish long-term potentiation in memory formation. PKC is not a single enzyme but a family of serine/threonine kinases. At least eleven closely related PKC isozymes have been reported that differ in their structure, biochemical properties, tissue[..]

Alkylating agents are compounds that cause cytotoxic DNA damage as well as collateral mutagenic damage. They work by adding an alkyl group to the guanine base of the DNA molecule and cause breakage of DNA strands. Methylation at the guanine O6 position forms the greatest promutagenic and lethal toxic DNA lesion. O(6)-methylguanine (O6-meG)  is formed in DNA by alkylation of the oxygen atom of guanine, most often by N-nitroso compounds (NOC) and sometimes due to methylation by other compounds such as endogenous S-adenosyl methionine. Several repair pathways like direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. Direct reversal repair eliminates[..]

Development of a proper immune system requires the selection of lymphocytes expressing a useful repertoire of antigen receptors that can respond to foreign or dangerous antigens but not to self. For T-Cells developing in the thymus, these selection processes include both positive and negative selection of immature CD4 and CD8 cells, helping shape the mature T-Cell repertoire. These processes are regulated in large part through the interactions between the TCR (T-Cell Antigen Receptor) expressed on a given thymocyte and peptides presented in the context of either Class-II or Class-I MHC molecules. In T-Cells, at least three Tec Kinases are expressed: Tec, RLK (Resting Lymphocyte Kinase)/TXK and ITK (Inducible T-Cell Kinase), which have expression primarily restricted to[..]