Estrogens play important roles in growth, development, reproduction, and maintenance of a diverse range of mammalian tissues. The physiological effects of estrogens are mediated by the intracellular ERs (Estrogen Receptors), which regulate transcription of target genes through binding to specific DNA target sequences. The ERs orchestrate both transcriptional and non-genomic functions in response to estrogens, xenoestrogens and signals emanating from growth factor signalling pathways. The pleiotropic and tissue-specific effects of estrogens are mediated by the differential expression of two distinct ER subtypes: ER-Alpha and ER-Beta, and their coregulators (Ref.1). The activities of a plethora of ER-interacting proteins converge to confer distinct functionalities on[..]

Epstein-Barr virus (EBV) is a gamma-herpesvirus that infects more than 90% of people worldwide, is the etiologic agent of infectious mononucleosis, and is associated with multiple human malignancies, primarily of lymphoid and epithelial cell origin, including Burkitt’s lymphoma, post-transplant lymphoma, AIDS-associated lymphomas, Hodgkin’s disease, T-Cell lymphoma, NPC (Nasopharyngeal Carcinoma), parotid gland carcinoma, and gastric carcinoma. EBV-encoded RNAs (EBERs) are the most abundant viral transcripts in latently EBV-infected cells (Ref.1). The canonical NF-kappaB pathway plays a pivotal role in regulating a variety of essential processes, such as immunity, cell survival, and proliferation. A large number of both positive and negative regulators of NF-kappaB[..]

A recurring theme in neurobiology is the role of a set of molecules that support proliferation, differentiation and survival of neurons. These molecules, collectively referred to as neurotrophins, are essential for the development and maintenance of the vertebrate nervous system, mediating their signal into the cell by specific interaction with tyrosine kinase receptors of the TRK (Tyrosine Kinase Receptor) family. TRK family is composed of related transmembrane tyrosine receptor kinases that specifically bind neurotrophins: TRKA binds NGF (Nerve Growth Factor); TRKB binds BDNF (Brain Derived Neurotrophic Factor), NT3 (Neurotrophin-3) and NT4/5 (Neurotrophin-4/5); and TRKC binds NT3. Out of these, TRKA forms a high-affinity binding site for NGF, the best characterized[..]

Thrombin is a multifunctional serine protease involved in a number of pathophysiological processes that include blood clotting, inflammation, repair processes and tumor metastasis. In brain, thrombin regulates the viability of neurons and astrocytes by increasing survival under conditions of hypoglycemia and oxidative stress and inducing apoptosis under other conditions. Thrombin is also chemotactic for macrophages and mitogenic for smooth muscle cells, fibroblasts, and astrocytes and induces secretion of growth factors and cytokines from fibroblasts and smooth muscle cells. Most of the thrombin-mediated effects are preceded by morphological changes in cells that follow activation of PARs (Protease-Activated Receptors) (Ref.1).PARs are a unique class of heterotrimeric,[..]

Signals that derive from cell adhesion to the ECM (Extracellular Matrix) regulate important physiological events including cell motility and growth, and most often involve changes in the organization of the actin cytoskeleton. Cells interact with the ECM via transmembrane receptors, termed integrins, located at the cell surface. Binding of integrins to the ECM is accompanied by a localized clustering of these receptors, with the subsequent recruitment of structural and signaling molecules to the sites of matrix attachment, focal contacts, providing links to the actin cytoskeleton (Ref.1). Numerous proteins present at the cytoplasmic face of FA (Focal Adhesions) include cytoskeletal proteins such as vinculin and talin. In addition, numerous "signaling"[..]

Cell division is characterized by orchestrated events of chromosome segregation, distribution of cellular organelles, and the eventual partitioning and separation of the two daughter cells. Mitosis is a highly regulated process that assures the proper allotment of genetic material between each pair of daughter cells. It proceeds through successive stages of well-defined and coordinated sub-processes. Entry into mitosis is regulated by the CDC2 (Cell Division Cycle-2)/Cyclin-B heterodimer. CDC2/Cyclin-B activity drives the events of early mitosis, such as nuclear breakdown, chromosome condensation and spindle formation by phosphorylating cellular substrates. While CDC2 (the catalytic subunit of the heterodimer) is required to drive the events of early mitosis,[..]

p53 is a tumour suppressor protein that regulates the expression of a wide variety of genes involved in Apoptosis, Growth arrest, Inhibition of cell cycle progression, Differentiation and accelerated DNA repair or Senescence in response to Genotoxic or Cellular Stress. As a transcription factor, p53 is composed of an N-terminal Activation Domain, a central specific DNA Binding Domain, and a C-terminal Tetramerization Domain, followed by a Regulatory Domain rich in basic Amino acids. Having a short half-life, p53 is normally maintained at low levels in unstressed mammalian cells by continuous ubiquitylation and subsequent degradation by the 26S Proteasome. Nonphosphorylated p53 is ubiquitylated by the MDM2 (Mouse Double Minute-2) ubiquitin ligase. MDM2 binding[..]

Nuclear factor-kappaB (NF-kappaB) comprises a family of transcription factors that regulate the expression of genes encoding proteins and microRNAs (miRNA, miR) precursors and may regulate a variety of biological processes such as inflammation, immunity, cell proliferation, differentiation, survival, cancer development, and progression (Ref.1, 2 and 3). NF-kappaB is ubiquitously expressed and responds to diverse stimuli, including infectious agents, cytokines, or growth factors. NF-kappaB /Rel family include five members, namely RELA (p65), RELB, c-REL, p50, and p52, all comprising a conserved REL homology domain (RHD) near the N-terminus, which are able to form homo- or heterodimers with the ability to transmit receptor signals to the nucleus. Although NF-kappaB is[..]

The C (Complement) system consists of about twenty 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. Activation of the complement system initiates a series of enzymatic reactions in which the proteolytic cleavage and activation of successive complement proteins leads to the covalent bonding or fixing of complement fragments to the pathogen surface. A major consequence of this is the uptake and destruction of complement coated microbes by phagocytes that bear receptors for these complement[..]

Covalent modifications of proteins, such as phosphorylation, acetylation and ubiquitylation, play an important role in most cellular processes because they can cause rapid changes in the activities of pre-existing proteins. This type of mechanism for regulating protein function is especially crucial in signal transduction pathways and in cell cycle. Posttranslational modifications (PTMs) by members of the ubiquitin family are covalent events that promote radical changes in the properties of modified proteins. Among all ubiquitin-like molecules, a particular attention has been given to the modification by SUMO (Small Ubiquitin Modifier) also known as Sentrin. SUMOylation plays critical roles in a variety of cellular processes, including transcription, cellular[..]

Apoptosis is a naturally occurring process by which a cell is directed to Programmed Cell Death. Apoptosis is based on a genetic program that is an indispensable part of the development and function of an organism. In this process, cells that are no longer needed or that will be detrimental to an organism or tissue are disposed of in a neat and orderly manner; this prevents the development of an inflammatory response, which is often associated with Necrotic cell death. There are at least two broad pathways that lead to Apoptosis, an "Extrinsic" and an "Intrinsic" Pathway. In both pathways, signaling results in the activation of a family of Cys (Cysteine) Proteases, named Caspases that act in a proteolytic cascade to dismantle and remove the dying cell. The extrinsic[..]

mTOR (Mammalian Target of Rapamycin) is a 289-kDa serine/threonine protein kinase and a member of the PIKK (Phosphatidylinositol 3-Kinase-related Kinase) family. The protein consists of a Catalytic Kinase domain, an FRB (FKBP12–Rapamycin Binding) domain, a putative Auto-inhibitory domain (Repressor domain) near the C-terminus and up to 20 tandemly repeated HEAT motifs at the Amino terminus, as well as FAT (FRAP-ATM-TRRAP) and FATC (FAT C-terminus) domains. The C-terminus of TOR is highly homologous to the catalytic domain of PI3K (Phosphatidylinositol 3-Kinase). mTOR proteins are evolutionarily conserved from yeast to human in the C-domain, with human, mouse, and rat mTOR proteins sharing 95% identity at the amino acid level. The human mTOR gene encodes a protein[..]