Volume 3, Issue 6

Trophoblast implantation and placentation allow the survival of the young embryo and its normal development inside the uterus. In order for these processes to function properly, the trophoblast has to undergo a series of characteristic changes that lead to its adhesion and invasion of the uterus. This is achieved, among other mechanisms, by inactivation of specific tumor suppressor genes, commonly by methylation of their promoters. Cell adhesion and tissue invasion are also characteristics of malignant tumors and patterns of methylation similar to that seen in trophoblast are found in various tumor types. Another important mechanism that aids trophoblast cells invasion is their transition from epithelial to mesenchymal phenotype. Such a transition is also a common characteristic of invading malignant cells. Thus, studying tissue invasion and its control mechanisms can benefit the understanding of both the trophoblast and malignant cells behavior.

Glucocorticoids, recognized as stress-related steroid hormones secreted from adrenal glands, have multiple roles in brain function. The concentration of glucocorticoids is regulated by the hypothalamic-pituitary-adrenal axis, and chronically elevated levels of glucocorticoids are putatively involved in the pathophysiology of mental disorders, such as depression. As corticosteroids are also widely used as medical drugs (e.g., for chronic lung disease in infants), the developmental influence of glucocorticoids on neuronal survival and synaptic plasticity is a critical concern. Although many reports suggest a biological effect of glucocorticoids on neuronal populations of the central nervous system (CNS), some reports suggest a possibility that glial responses (including regulation of neurotrophic factor expression) to glucocorticoids are different from that of neurons. In the present review, we show an overview of the current knowledge concerning the impact of glucocorticoids on behavior in animal models of depression, and on cell survival and function in the CNS.

Appropriate establishment and maintenance of cell polarity is essential for normal development and homeostasis. The vast majority of human cancers originate from epithelial tissues and tumour cell invasion and metastasis are the major cause of mortality in human cancers. Invading cells demonstrate loss of cell polarity, loss of epithelial cell-cell adhesions and tissue disorganisation. We examine the growing evidence linking loss of apicobasal polarity with tumour progression.

The review focuses on the mechanism of mismatch repair in bacteriophage T4. It was first observed in T4 as an extra recombination mechanism, which contributed to the general recombination only when particular rII mutations were used as genetic markers (high-recombination markers), whereas it was inactive toward other rII mutations (low-recombination markers). This marker-dependent recombination pathway was identified as a repair of mismatches in recombinational heteroduplexes. Comparison of the structure of markers enabled us to make several specific conclusions on the nature of the marker discrimination by the mismatch repair system operating during T4 crosses. First, heteroduplexes with one mismatched base pair (either of transition or of transversion type) as well as single-nucleotide mismatches of indel type are not efficiently repaired. Second, among the repairable mismatches, those with two or more contiguous mismatched nucleotides are the most effectively repaired, whereas insertion of one correct pair between two mismatched ones reduces the repairability. Third, heteroduplexes containing insertion mutations are repaired asymmetrically, the longer strand being preferentially removed. Fourth, the sequence environment is an important factor. Inspection of the sequences flanking mismatches shows that runs of A:T pairs directly neighboring the mismatches greatly promote repair. The mismatch is recognized by T4 endonuclease VII and nicked on the 3′ side. The nonpaired 3′ terminus is attacked by the proofreading 3′→5′ exonuclease of T4 DNA polymerase that removes the mismatched nucleotides along with several (~25) complementary nucleotides (the repair tract) and then switches to polymerization. The residual nick is ligated by DNA ligase (gp30). Most probably, the T4 system repairs replication and other mismatches as well; however, it might not discriminate old and new DNA strands and so does not seem to be aimed at repair of replication errors, in contrast to the most commonly studied examples of mismatch repair.

Cyclin A2 belongs to the core cell cycle regulators and participates in the control of both S phase and mitosis. However, several observations suggest that it is also endowed with other functions, and our recent data shed light on its involvement in cytoskeleton dynamic and cell motility. From the transcription of its gene to its posttranslational modifications, cyclin A2 regulation reveals the complexity of the regulatory network shaping cell cycle progression. We summarize our current knowledge on this cell cycle regulator and discuss recent findings raising the possibility that cyclin A2 might play a much broader role in epithelial tissues homeostasis.

Argonaute proteins play a central role in gene silencing pathways mediated by small RNA molecules. The ancestral function of small RNA-dependent silencing is related to genome protection against parasitic nucleic acids, such as transposons and viruses. However, new classes of small RNAs are continuously being uncovered in all higher eukaryotes in which they play important functions in processes ranging from embryonic development to differentiation to cell proliferation and metabolism. Small RNAs have variegated biogenesis pathways and accomplish distinct functions. Nevertheless, it appears that all small RNAs work merely as guides in recognizing the target RNAs invariably relying on the interaction with Argonaute proteins and associated factors for their biological function. Here, we discuss recent findings on the structure and regulation of mammalian Argonaute proteins and overview the various roles that these versatile proteins play in regulating gene expression.

Members of the p24 protein family form a highly conserved family of type I transmembrane proteins that are abundant components of the early secretory pathway. Topologically, the proteins have a large luminal domain and a short cytoplasmic domain that allows for targeting to both coat protein complex II and coat protein complex I vesicles, and thus these proteins cycle between the endoplasmic reticulum and Golgi compartments. Several functions have been proposed for these proteins including a role in coat protein complex I vesicle biogenesis, cargo protein selection, organization of intracellular membranes, and protein quality control. Recent studies have added to the list of potential cargo substrates for which p24 function is required for normal transport in the secretory pathway. This review focuses on recent developments in the study of p24 proteins and their requirement for secretory and membrane protein transport in eukaryotic cells.

The eukaryotic cytoskeleton is a vulnerable target of many microbial pathogens during the course of infection. Rearrangements of host cytoskeleton benefit microbes in various stages of their infection cycle such as invasion, motility, and persistence. Bacterial pathogens deliver a number of effector proteins into host cells for modulating the dynamics of actin and microtubule cytoskeleton. Alteration of the actin cytoskeleton is generally achieved by bacterial effectors that target the small GTPases of the host. Modulation of microtubule dynamics involves direct interaction of effector proteins with the subunits of microtubules or recruiting cellular proteins that affect microtubule dynamics. This review will discuss effector proteins from animal and human bacterial pathogens that either destabilize or stabilize host microtubules to advance the infectious process. A compilation of these research findings will provide an overview of known and unknown strategies used by various bacterial effectors to modulate the host microtubule dynamics. The present review will undoubtedly help direct future research to determine the mechanisms of action of many bacterial effector proteins and contribute to understanding the survival strategies of diverse adherent and invasive bacterial pathogens.

Neonates of most species depend on milk lipids for calories, fat-soluble vitamins, and bioactive lipid components for growth and development during the postnatal period. To meet neonatal nutrition and development needs, the mammary gland has evolved efficient mechanisms for synthesizing and secreting large quantities of lipid during lactation. Although the biochemical steps involved in milk lipid synthesis are understood, the identities of the genes mediating these steps and the molecular physiology of milk lipid production and secretion have only recently begun to be understood in detail through advances in mouse genetics, gene expression analysis, protein structural properties, and the cell biology of lipid metabolism. This review discusses emerging data about the molecular, cellular, and structural determinants of milk lipid synthesis and secretion within the context of physiological functions.

Proteasome inhibitors are used as anticancer drugs, however, the precise mechanisms of their selective activity against cancer cells are not understood well. While proteasome inhibitors stabilize the majority of cellular proteins through inhibition of proteasome activity, they also paradoxically downregulate several other proteins. We recently discovered that proteasome inhibitors suppress mRNA and protein expression of FOXM1, NPM, and ARF proteins that are involved in cancer. We postulated that proteasome inhibitors preferentially stabilize negative regulators of transcription of these genes, which overrides their protein stabilization. These data suggest a presence of multiple secondary mechanisms that may regulate transcription, degradation, or localization of cellular proteins after treatment with proteasome inhibitors. Future experiments will identify these mechanisms and additional proteins suppressed by proteasome inhibitors, and will help explain the role of protein suppression by proteasome inhibitors in their anticancer activity.