The integrity of genetic information depends on the fidelity of DNA replication and on the efficiency of several different DNA repair processes. Among many types of DNA repair, the general MMR (DNA Mismatch Repair) pathway is responsible for correcting base substitution mismatches which is generated during DNA replication in organisms from bacteria to mammals. The MMR system improves the fidelity of DNA synthesis by 100-1000 fold. The MMR also corrects IDLs (Insertion-Deletion Loops) which may occur during replication and recombination of DNA. MMR also able to correct DNA damages caused by internal or external sources. Inactivation or deterioration of this pathway has been linked to a variety of cancers, most notably Hereditary Non-Polyposis Colorectal Cancer. MMR can[..]

OX40 is an approximately 50-kD transmembrane glycoprotein of 249 amino acids, with a 49 amino acid cytoplasmic tail and a 186 amino acid extracellular region. It is a member of the TNFR (tumor necrosis factor receptor) superfamily and has three complete and one truncated cysteine-rich domains. It is a T-Cell activator that is believed to promote the survival (and perhaps prolong the immune response) of CD4+ T cells at sites of inflammation (Ref.1). OX40’s ligand (OX40L, also known as gp34, CD252, TNFSF4), a member of the TNF (Tumor Necrosis Factor) super family, is a 32 kDa protein, which has about 183 aa residue glycosylated polypeptide that consists of a 23 amino acid cytoplasmic tail and a 133 amino acid extracellular domain. It is a type II glycoprotein that[..]

B lymphoid cells are essential for the humoral immune response by producing a diverse range of antigen-specific antibodies. Antibody-mediated immunity is provided by two distinctive B cell lineages that diverge early in life. The better-known conventional, or B2, B cells provide adaptive immunity by producing high-affinity pathogen-specific antibodies, typically in a T cell-dependent manner. The pool of B2 cells is constantly replenished from hematopoietic stem and progenitor cells in the bone marrow [Ref.1]. B1a cells provide innate-like immunity by producing “natural” low-affinity, broad-specificity antibodies against a wide range of overlapping antigens, including self-antigens. In contrast to B2 cells, the pool of B1a cells is largely established at[..]

p21-activated kinase (PAK) family of serine/threonine protein kinases are downstream effectors of the Rho family of GTPases (Rac and Cdc42). PAKs are found in most eukaryotes and play an evolutionarily conserved role in many cellular processes like cell proliferation, survival, gene transcription, transformation, and cytoskeletal remodeling (Ref.1). There are six PAK isoforms identified in humans that share a conserved catalytic domain located at the C-terminus. They have been classified into two groups (I and II) according to the similarity of their catalytic domains, and regulatory mechanisms. The C-terminal kinase catalytic domain is similar among all human PAKs where as the N-terminal regions are more variable. Group I PAKs consists of (isoforms 1, 2 and 3) where[..]

The actin family is a diverse and evolutionarily ancient group of proteins that provide the supportive framework to the three-dimensional structure of eukaryotic cells. It provides the forces that enable the cell to adopt a variety of shapes and to undertake directed movements. Certain cell types, such as polymorphonuclear leukocytes, monocyte/macrophages, and metastatic cells, are able to move rapidly through tissues and these movements are mediated by the actin cytoskeleton (Ref.1). An important property of actin is its ability to produce movement in the absence of motor proteins. At the cell membrane actin microfilament assembly protrudes the membrane forward producing the ruffling membranes in actively moving cells. These microfilaments also play a passive[..]

Ras is a membrane-associated guanine nucleotide-binding protein that is normally activated in response to the binding of extracellular signals, such as growth factors, RTKs (Receptor Tyrosine Kinases), TCR (T-Cell Receptors) and PMA (Phorbol-12 Myristate-13 Acetate). Ras signaling affects many cellular functions, which includes cell proliferation, apoptosis, migration, fate specification, and differentiation. Ras acts as a binary signal switch cycling between ON and OFF states, which are characterized in terms of a small molecule, a guanine nucleotide, bound to the protein. In the resting cell, Ras is tightly bound to GDP (Guanosine Diphosphate), which is exchanged for GTP (Guanosine Triphosphate) upon binding of extracellular stimuli to cell membrane receptors. In the[..]

Complement is a system of circulating enzymes that is part of the body's response to illness or injury. The complement system plays an essential role in host defence against infectious agents and in the inflammatory process. It consists of about thirty plasma proteins that function either as enzymes or as binding proteins. In addition to these plasma proteins, the complement system includes multiple distinct cell-surface receptors that exhibit specificity for the physiological fragments of complement proteins and that occur on inflammatory cells and cells of the immune system. There are also several regulatory membrane proteins that function to prevent autologous complement activation and protect host cells from accidental complement attack. The complement system can[..]

Irradiation of DNA by UV (Ultraviolet light) causes lesions, such as Cyclobutane-Pyrimidine Dimers or 6-4PPs (6-4 Pyrimidine Pyrimidone). The most common covalently linked adjoining pyrimidines are T-T (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 these lesions are fatal if they go[..]

8-oxo-7,8-dihydroguanine (8-oxoG) is a pre-mutagenic DNA lesion that is formed by the oxidation of guanine. Reactive oxygen species (ROS) that is primarily responsible for the damage of guanine is produced as a result of several endogenous processes or environmental agents. ROS can cause damage to cellular macromolecules like proteins, lipids and nucleic acids. Proteins, proteins, lipids and RNA having oxidative damage are generally degraded and recycled, whereas DNA lesions like 8-oxoG need to be repaired to maintain genomic integrity (Ref.1 and 2). 8-oxoG is generally repaired in human through base excision repair (BER) pathway. The enzyme human 8-oxoG DNA glycosylase 1 (HOGG1) is the primary enzyme that initiates the repair of 8-oxoG. OGG1 initiated BER[..]

The cellular response to O2 (oxygen) is a central process in animal cells and figures prominently in the pathophysiology of several diseases, including cancer, cardiovascular disease, and stroke. This process is coordinated by the HIF (Hypoxia-Inducible Factor) and its regulator, the pVHL (Von Hippel-Lindau tumor suppressor protein). HIF1 is a basic helix-loop-helix transcription factor that transactivates genes encoding proteins that participate in homeostatic responses to hypoxia. It induces expression of proteins controlling glucose metabolism, cell proliferation, and vascularization. Several genes involved in cellular differentiation are directly or indirectly regulated by hypoxia. These include Epo (Erythropoietin), LDHA (Lactate Dehydrogenase-A), ET1[..]

Cardiac failure, one of the largest health care burdens in the United States and other developed countries is often associated with prolonged and maladaptive cardiac hypertrophy, defined as a compensatory mechanism of the heart that helps to maintain cardiac output during pathological states with sustained increases in hemodynamic load (Ref.1). As cardiomyocytes lose the ability to divide soon after birth, cardiac hypertrophy offers an important adaptive response in vivo that allows the organism to maintain or increase its cardiac output. The adult myocardium responds to a wide array of intrinsic and extrinsic stimuli, including hypertension, myocardial infarction, cardiac arrhythmias, valvular disease, endocrine disorders, increased workload, injury, and[..]

4-1BB is an inducible T cell surface receptor belonging to the tumor necrosis factor receptor super family. It presents on the surfaces of activated CD4+ and CD8+ T cells, monocytes and B lymphocytes. 4-1BB signaling is activated by binding to its high-affinity ligand 4-1BBL which is expressed on the surface of antigen-presenting cell. 4-1BB signaling promotes cell growth, T cell differentiation and survival of immune cells (Ref.1&2).4-1BB mediates its action via association with TRAF1, TRAF2 and TRAF3. 4-1BB binding to TRAF2 and TRAF3/ cIAP complex leads to activation of the NIK. NIK activates NF-kB via the IKK-alpha/ NFKBIA pathway (Ref.2, 3, 4&5).NF-kB induces transcription of Bcl-XL, Bcl-2 and BFL1, and thus promotes survival of immune cells (Ref.6,[..]