DNA methylation is one of the best characterized epigenetic modifications. In mammals it is involved in various biological processes including the silencing of transposable elements, regulation of gene expression, genomic imprinting, and X-chromosome inactivation.DNA methylation of gene promoter regions is associated with transcription repression.Transcriptional repression is an essential mechanism in the precise control of gene expression. Transcriptional repressor proteins associate with their target genes either directly through a DNA-binding domain or indirectly by interacting with other DNA-bound proteins. To inhibit transcription in a selective manner, a repressor protein can mask a transcriptional activation domain, block interaction of an activator with other[..]

Genotoxic stress is an important and ubiquitous type of stress that cells are inevitably exposed to over the life span of an organism. Many potentially damaging agents both from the environment and from endogenous processes involving activated oxygen species and other reactive agents can damage the DNA in cells (Ref.1). GADD45 induction by BRCA1 leads to programmed cell death through the JNK pathway via interaction with the upstream kinase MTK1/MEKK4. JNK has been shown to be involved in the induction of apoptosis after genotoxic stress and UV radiation. However, JNK and p38 may exert antagonistic effects depending on cell context, cross-talk with other signaling pathways and intensity and duration of the stimulus. Originally, JNK activation and inhibition experiments[..]

Cellular DNA is constantly exposed to the effects of endogenous or environmental agents such as free radicals, radiation and chemicals. In higher organisms, these nucleic alterations are estimated at several thousands of lesions per cell which can correspond to the loss of bases and also to the breaking of one or both strands of the DNA double helix. Among these DNA breaks, the DSB(double-strand break) is the most harmful because it is the most difficult to repair. DSBs are the most genotoxic DNA lesions.Unrepaired DSBs can lead to cell death, whereas misrepaired DSBs increase the likelihood of chromosome rearrangement, mutagenesis and loss of crucial genetic information. In replicating cells, such instability can result in apoptosis or cellular transformation. In[..]

Anthrax is a severe, although rather rare, infectious disease that is caused by the Gram-positive, spore-forming bacterium Bacillus anthracis. The infectious form is the spore and the major virulence factors of the bacterium are its poly-Gamma-D-glutamic acid capsule and the tripartite anthrax toxin. The discovery of the anthrax toxin receptors in the early 2000s has allowed in-depth studies on the mechanisms of anthrax toxin cellular entry and translocation from the endocytic compartment to the cytoplasm. There are three forms of anthrax disease defined by the route of spore entry into the body: cutaneous, gastrointestinal, and inhalational anthrax. Early studies showed that spores are phagocytosed by resident macrophages and dendritic cells, which may serve as a[..]

The MAPK (Mitogen-Activated Protein Kinase) cascades play a pivotal role in many aspects of cellular functions, and are evolutionarily conserved from yeast to mammals. In Saccharomyces. cerevisiae, there are five MAP kinase signal transduction pathways that regulate mating, filamentous growth, high osmolarity response, maintenance of cellular integrity, and ascospore formation. The best-defined yeast MAPK pathway in S. cerevisae is involved in the mating of haploid cells. Yeast may exist either as haploid or diploid cells. The haploid cells have two sexual phenotypes characterized by the expression of a set of genes involved in mating that are not expressed in diploids. The mating response to generate diploids is stimulated by the release of small peptide mating[..]

14-3-3 proteins are abundantly expressed adaptor proteins that interact with a vast number of binding partners to regulate their cellular localization and function. They regulate substrate function in a number of ways including protection from dephosphorylation, regulation of enzyme activity, formation of ternary complexes and sequestration. They are key regulators of major cellular processes such as proliferation, differentiation, senescence and apoptosis (Ref.1 and 2). Apoptosis is a physiological process of cell death that plays a critical role in normal development as well as in the pathophysiology of a variety of diseases. The fundamental cellular mechanism behind apoptosis is due to a balance between anti-apoptotic and pro-apoptotic factors, which may be shifted[..]

SARS (Severe Acute Respiratory Syndrome) is a newly emerged infection in humans characterized by fever and pneumonia. This disease may progress rapidly to ARDS (Acute Respiratory Distress Syndrome) with considerable morbidity and mortality. It was first identified in the Guandong Province of China in November 2002, and a major outbreak occurred in Hong Kong in March 2003 (Ref.1). Probable cases have been reported in 31 countries, with extensive ongoing transmission in Taiwan and China, continuing transmission in Hong Kong, and major outbreaks that are now under control in Singapore and Vietnam. There are three different phases of SARS, with symptoms including fever, a dry cough, dyspnea (shortness of breath), headache, and hypoxaemia (low blood oxygen concentration).[..]

Asthma is a complex, chronic inflammatory lung disease which is characterized by persistent airway inflammation and airway wall remodeling, that includes the structural changes in the airway wall, epithelial cell shedding, hyperplasia and hypertrophy of the ASM (airway smooth muscle) bundles, basement membrane thickening and increased vascular density. Airway wall remodeling starts early in the pathogenesis of asthma [Ref.1]. It originates from complex interactions between genetic factors and environmental agents such as aeroallergens and respiratory viruses [Ref.2]. In the airway lumen, TSLP, IL-25, and IL-33 acts directly on dendritic cells and then it processes the antigenic molecules and present them to Th0 (naïve T helper cells) [Ref.3]. Further, Th0 get[..]

Chronic obstructive pulmonary disease (COPD) is a major global health problem that is becoming preva¬lent, particularly in developing countries [Ref.1]. It is one of the most common diseases in the world, with a lifetime risk estimated to be as high as 25%, and now equally affects both men and women [Ref.2]. COPD is greatly under¬ diagnosed and often diagnosed late in its course, so there are vigorous attempts to increase awareness of this dis¬ease and to promote the use of spirometry to identify more patients [Ref.3]. COPD involves chronic inflammation of the periph-eral airways and lung parenchyma, which leads to pro¬gressive narrowing of the airways and shortness of breath [Ref.4.]Cigarette smoke (and other irritants) activates macrophages and[..]

More than 200 different types of viruses, such as human Rhinovirus (HRV), human Metapneumovirus (HMPV), Respiratory Syncytial Virus (RSV), and human Parainfluenza Virus (HPIV), are known to cause acute respiratory illness. Virus-induced cytokine production and inflammatory cell activation are instrumental in the development of neurogenic inflammatory responses, and these combined factors increase bronchoconstriction in response to allergens or irritants. Respiratory viruses primarily infect and replicate within airway epithelial cells. During the replication process, the cells release antiviral factors and cytokines that alter local airway inflammation and airway niche. In a healthy airway, the inflammation normally leads to type 1 inflammatory responses consisting of[..]

Many proto-oncogenes participate in the regulation of apoptosis and closely intertwined with their actions are various growth factors and other genes that participate in the control of cellular growth. The proto-oncogene c-Myc encodes a transcription factor c-Myc that plays a critical role in multiple cellular processes including cell growth, proliferation, differentiation, and apoptosis. Expression of c-Myc is rapidly induced by mitogens and is down regulated during differentiation. c-Myc activity is sufficient to drive cells into the cell cycle in the absence of growth factors but also induces apoptosis when survival factors are missing. Deregulated expression of c-Myc is associated with a wide array of human cancers. Thr-58 is a major phosphorylation site in c-Myc[..]

FLT3 (Fms-like Tyrosine Kinase-3), also known as FLK2 (Fetal Liver Kinase-2) and STK1 (human Stem Cell Kinase-1) was originally isolated as a hematopoietic progenitor cell-specific kinase, and belongs to the Class-III RTK (Receptor Tyrosine Kinase) family to which c-Fms, c-Kit, and the PDGFR (Platelet Derived Growth Factor Receptor) also belong (Ref.1). Normal expression of FLT3 is restricted to haemopoietic progenitor cells in the bone marrow, thymus and lymph nodes, but is also found on other tissues such as placenta, brain, cerebellum and gonads. Aberrantly expressed FLT3 is observed at high levels in a spectrum of hematologic malignancies including 70% to 100% of AML (Acute Myelogenous Leukemia), B-precursor cell ALL (Acute Lymphoblastic Leukemia), a fraction of[..]