CTLs (Cytotoxic T Lymphocytes) and NK (Natural Killer) cells are the key immune effectors that eradicate infected cells or tumors. To destroy these targets, CTLs and NK cells mostly use the granule exocytosis pathway, which releases perforin and Granzymes from cytolytic granules into the immunological synapse formed with the target. Granzyme-A and Granzyme-B, the most abundant Granzymes, are delivered to the target cell cytosol through perforin and independently induce cell death. The tryptase Granzyme-A activates cell death through a caspase-independent mechanism. Granzyme-A causes characteristic features of apoptosis, including membrane blebbing, loss of mitochondrial transmembrane potential, nuclear fragmentation and chromatin condensation; however, instead of[..]

Cells are constantly under threat from the cytotoxic and mutagenic effects of DNA damaging agents that result from either endogenous sources (cellular metabolic processes) or exogenous sources (environmental factors). Endogenous sources of DNA damage include hydrolysis, oxidation, alkylation, and mismatch of DNA bases; sources for exogenous DNA damage include ionizing radiation (IR), ultraviolet (UV) radiation, and various chemicals agents (Ref.1). Repairing damage in DNA from anything that causes a mutation, such as UV radiation and tobacco smoke, is a fundamental process that protects our cells from becoming cancerous. The major forms of DNA damage include SSB (Single-strand Breaks), DSB (Double-strand Breaks), alteration of bases, hydrolytic depurination, hydrolytic[..]

WNT signaling pathways play essential roles in cellular proliferation, differentiation and cell migration during embryonic development. The importance of WNT signaling is indicated by conservation of its molecular components across organisms ranging from nematodes to humans. WNT pathways are classified into canonical WNT/CTNNB or non-canonical (β-catenin-independent) pathways. Canonical WNT/β- catenin signaling is the most studied, and is mediated by nuclear translocation of its central effector CTNNB and Non-canonical WNT signaling occurs independently of CTNNB–TCF/LEF and is stimulated by WNT ligands that bind to a receptor complex of FZD, ROR1/2 or RYK.WNT pathway is implicated in a variety of cancers (Ref.1 and 2).WNT ligands signal via seven[..]

Hydrolytic deamination of cytosine to uracil is a major source of genome instability in human cells.  This mutagenic process is mostly enhanced in single stranded DNA . Single stranded DNA can be found in transcribed genes, near forks, in mitochondrial DNA as well as in breathing DNA. It is believed to be much higher in replicating cells as compared to non-replicating cells. The cytosine deamination to uracil needs to be repaired soon to restore genomic stability. Otherwise uracil residues may give rise to C→T transitions, which are the most common spontaneous mutations occurring in living organisms. Uracil in DNA arises by spontaneous deamination of cytosine to generate pro-mutagenic U:G mispairs. Uracil in DNA is also produced by the incorporation of dUMP[..]

Innate immune system plays an important role in immune responses against pathogen invasion in vertebrates and invertebrates. In mammalian systems, it provides the first line of defense against multiple pathogens, whereas in insects, the entire immune system is innate. The Toll pathway plays important functions in innate immunity against infectious pathogens in vertebrates and invertebrates. Activation of the Toll pathway is different between vertebrates and invertebrates. In vertebrates like Homo sapiens, Toll pathway is directly activated by Toll-like receptors (TLRs) binding to various pathogen-associated molecular patterns (PAMPs) from different pathogens, whereas in invertebrates like Drosophila, Toll receptors bind to the cytokine-like molecule Spätzle but not to[..]

IP3 (Inositol 1,4,5-triphosphate), also known as a second messenger, is a molecule that functions to transfer a chemical signal received by the cell, such as from a hormone, neurotransmitters, growth factors and hypertrophic stimuli such as AngII (Angiotensin-II), Beta-adrenergic receptor agonists, and ET1 (Endothelin-1) to various signaling networks within the cell. IP3 is known to play a crucial role in initiating and propagating these messages; however, the precise mechanism of how IP3 relates to the next element in its signaling pathway, the calcium wave, remains highly controversial. The receptors for IP3, IP3R (IP3 Receptor) constitute a family of Ca2+ channels responsible for the mobilization of intracellular Ca2+ stores. Three different receptor types have been[..]

Mitochondrial fatty acid oxidation (FAO) and its key rate-limiting enzyme, the carnitine palmitoyltransferase (CPT) system, are important for energy homeostasis in situations like fasting or during exercise. They also regulate host immune responses and the deficiency or over-activation of CPT may cause energy metabolism disorder that may lead to many diseases starting from inflammatory disorders to cancer.  Fatty acid catabolism occurs mostly in mitochondria through the beta-oxidation pathway (Ref.1 and 2). Long-chain fatty acids (LCFA), major component of fatty acids, that are important source of energy for heart, liver and muscles, cannot enter the mitochondria by simple diffusion unlike short or medium chain fatty acids. LCFA are activated and converted to[..]

The Malate (L-Malic Acid)-Asp (Aspartate or L-Aspartate or Aspartic Acid) Shuttle of mammalian systems is more complex but more energy efficient. Mitochondrial NAD+ (Nicotinamide Adenine Dinucleotide) is reduced by cytosolic NADH (Nicotinamide Adenine Dinucleotide, Reduced) through the intermediate reduction and subsequent regeneration of OAA (Oxaloacetate) (Ref.1). In the cytosol, the shuttle converts OAA to Malate using the enzyme MDH1 (Malate Dehydrogenase-Cytoplasmic), and at the same time re-oxidizes NADH to NAD+, making it available for Glucose oxidation. Malate is then shuttled into the mitochondria by a Malate-Alpha-Ketoglutarate Transporter. In the mitochondria, the reverse reaction takes place and Malate is again converted to OAA by the enzyme MDH2 (Malate[..]

Androgens are recognized as genotropic inducers of a number of physiological functions mainly associated with the development of sexual characteristics. Androgens promote the growth and differentiation of prostate cells through ligand activation of the AR (Androgen Receptor) (Ref.1&2). The AR, upon activation by Androgens, mediates transcription of target genes that modulate growth and differentiation of prostate epithelial cells. AR signaling is crucial for the development and maintenance of male reproductive organs including the prostate gland (Ref.3). The majority of serum Androgens is complexed with the plasma glycoprotein SHBG (Sex Hormone-Binding Globulin). The plasma protein SHBG binds to a receptor SHBGR (Sex Hormone-Binding Globulin Receptor) on cell[..]

NF-KappaB (Nuclear factor-KappaB)/Rel proteins are dimeric, sequence-specific transcription factors involved in the activation of an exceptionally large number of genes in response to inflammation, viral and bacterial infections, and other stressful situations requiring rapid reprogramming of gene expression. NF-kappB pathway is crucial for the regulation of immune responses, inflammation, and stress responses. Rel/NF-KappaB transcription factors include a collection of proteins, conserved from the fruit fly Drosophila melanogaster to humans. The fruit fly Drosophila melanogaster has proved to be a valuable model system to study these evolutionarily conserved NF-KappaB mediated immune responses (Ref.1 and 2).NF-KappB pathways play a major role in Drosophila host[..]

Estrogen contributes to the development of three of the top five cancers of women--those of the breast, uterus, and ovaries--which together account for an estimated 240,000 new cancer cases a year in the United States alone (Ref.1). The ER (Estrogen Receptor) signaling pathway is implicated in the progression of cancer tumorigenesis and the activity of the hormone receptor is regulated by ligands (Estrogens), and coactivators or corepressors (Ref.2). MNAR (Modulator of Nongenomic Activity Of Estrogen Receptor)/PELP1 (Proline Glutamic Acid-Rich Nuclear Protein)/p160, a recently identified novel coactivator of ERs, has been shown to be amplified and overexpressed in breast cancer cell lines, whose expression in some cases, may be as high as, 3-5 times higher in breast[..]

Cell cycle checkpoints are surveillance mechanisms that monitor the order, integrity, and fidelity of the major events of the cell cycle. These include growth to the appropriate cell size, the replication and integrity of the chromosomes, and their accurate segregation at mitosis. Many of these mechanisms are ancient in origin and highly conserved, and hence have been heavily informed by studies in simple organisms such as the yeasts. Others have evolved in higher organisms, and control alternative cell fates with significant impact on tumor suppression.Recent work on the mechanisms of DNA damage and replication cell cycle checkpoints has revealed great similarity between the checkpoint pathways of organisms as diverse as yeasts, flies, humans and mouse. However, there[..]