Band 1, Heft 5-6

Numerous epigenetic modifications have been identified and correlated with transcriptionally active euchromatin or repressed heterochromatin and many enzymes responsible for the addition and removal of these marks have been characterized. However, less is known regarding how these enzymes are regulated and targeted to appropriate genomic locations. Mammalian CXXC finger protein 1 is an epigenetic regulator that was originally identified as a protein that binds specifically to any DNA sequence containing an unmethylated CpG dinucleotide. Mouse embryos lacking CXXC finger protein 1 die prior to gastrulation, and embryonic stem cells lacking CXXC finger protein 1 are viable but are unable to achieve cellular differentiation and lineage commitment. CXXC finger protein 1 is a regulator of both cytosine and histone methylation. It physically interacts with DNA methyltransferase 1 and facilitates maintenance cytosine methylation. Rescue studies reveal that CXXC finger protein 1 contains redundant functional domains that are sufficient to support cellular differentiation and proper levels of cytosine methylation. CXXC finger protein 1 is also a component of the Setd1 histone H3-Lys4 methyltransferase complexes and functions to target these enzymes to unmethylated CpG islands. Depletion of CXXC finger protein 1 leads to loss of histone H3-Lys4 tri-methylation at CpG islands and inappropriate drifting of this euchromatin mark into areas of hetero-chromatin. Thus, one function of CXXC finger protein 1 is to serve as an effector protein that interprets cytosine methylation patterns and facilitates crosstalk with histone-modifying enzymes.

All currently known structures of proteins together define ‘protein fold space’. To increase the general understanding of protein dynamics and protein folding, we selected a set of 807 proteins and protein domains that represent 95% of the currently known autonomous folded domains present in globular proteins. Native state and unfolding simulations of these representatives are now complete and accessible via a novel database containing over 11 000 simulations. Because protein folding is a microscopically reversible process, these simulations effectively sample protein folding across all of protein fold space. Here, we give an overview of how the representative proteins were selected and how the simulations were performed and validated. We then provide examples of different types of analyses that can be performed across our large set of simulations, made possible by the database approach. We further show how the unfolding simulations can be used to compare unfolding of structural elements in isolation and in different structural contexts, using as an example a short, triple stranded β-sheet that forms the WW domain and is present in several larger unrelated proteins.

RNA-binding proteins are involved in many important regulatory processes in cells and their study is essential for a complete understanding of living organisms. They show a large variability from both structural and functional points of view. However, several recent studies performed on protein-RNA crystal structures have revealed interesting common properties. RNA-binding sites usually constitute patches of positively charged or polar residues that make most of the specific and non-specific contacts with RNA. Negatively charged or aliphatic residues are less frequent at protein-RNA interfaces, although they can also be found either forming aliphatic and positive-negative pairs in protein RNA-binding sites or contacting RNA through their main chains. Aromatic residues found within these interfaces are usually involved in specific base recognition at RNA single-strand regions. This specific recognition, in combination with structural complementarity, represents the key source for specificity in protein-RNA association. From all this knowledge, a variety of computational methods for prediction of RNA-binding sites have been developed based either on protein sequence or on protein structure. Some reported methods are really successful in the identification of RNA-binding proteins or the prediction of RNA-binding sites. Given the growing interest in the field, all these studies and prediction methods will undoubtedly contribute to the identification and comprehension of protein-RNA interactions.

Many studies on the cholinergic pathway have indicated that cholinergic receptors, which are widely expressed in various cells, play an important role in all body organs. In this review, we present the concept that cholinergic responses are regulated through a neuronal or non-neuronal mechanism. The neuronal mechanism is a system in which acetylcholine binds to cholinergic receptors on target cells through the nerves. In the non-neuronal mechanism, acetylcholine, produced by neighboring cells in an autocrine/paracrine manner, binds to cholinergic receptors on target cells. Both mechanisms subsequently lead to physiological and pathophysiological responses. We also investigated the subunits/subtypes of cholinergic receptors on target cells, physiological and pathophysiological responses of the organs via cholinergic receptors, and extracellular factors that alter the subtypes/subunits of cholinergic receptors. Collectively, this concept will elucidate how cholinergic responses occur and will help us conduct further experiments to develop new therapeutic agents.

Oxytocin is a neurohypophyseal hormone that is produced centrally by neurons in the paraventricular nucleus and supraoptic nucleus of the hypothalamus. It is released directly into higher brain centres and into the peripheral circulation where it produces a multitude of effects. Classically, oxytocin is known for inducing uterine contractions at parturition and milk ejection during suckling. Oxytocin also acts in a species and gender specific manner as an important neuromodulator. It can affect behaviours associated with stress and anxiety, as well social behaviours including sexual and relationship behaviours, and maternal care. Additionally, oxytocin has been shown to have a variety of physiological roles in peripheral tissues, many of which appear to be modulated largely by locally produced oxytocin, dispelling the notion that oxytocin is a purely neurohypophyseal hormone. Oxytocin levels are altered in several diseases and the use of oxytocin or its antagonists have been identified as a possible clinical intervention in the treatment of mood disorders and pain conditions, some cancers, benign prostatic disease and osteoporosis. Indeed, oxytocin has already been successful in clinical trials to treat autism and schizophrenia. This review will report briefly on the known functions of oxytocin, it will discuss in depth the data from recent clinical trials and highlight future targets for oxytocinergic modulation.

Recent studies suggest that homeostasis of lipid metabolism is crucial for the function of various immune cells. Oxygenated derivatives of cholesterol (oxysterols) are well-known regulators of lipid metabolism and have diverse functions, such as inhibition of cholesterol synthesis, efflux of intracellular cholesterol, synthesis of cholesterol esters, and activation of liver X receptors (LXRs). In this review, we introduce novel roles of the oxysterol receptors LXRs in the immune system, including regulation of inflammatory responses, T cell expansion, immunoglobulin production, and antitumor responses. We also discuss lipid-mediated signaling as a potential target for treatment of immune diseases.

Akt (also known as protein kinase B or PKB) is the major downstream nodal point of the PI3K signaling pathway. This pathway is a promising anticancer therapeutic target, because constitutive activation of the PI3K-Akt pathway is correlated with tumor development, progression, poor prognosis, and resistance to cancer therapies. The Akt serine/threonine kinase regulates diverse cellular functions including cell growth, proliferation, glucose metabolism, and survival. Although all three known Akt isoforms (Akt1–3) are encoded by separate genes, their amino acid sequences show a high degree of similarity. For this and other reasons, it has long been assumed that all three Akt isoforms are activated in the same way, and their functions largely overlap. However, accumulating lines of evidence now suggest that the three Akt isoforms might have unique modes of activation and many distinct functions. In particular, it has recently been found that the Akt isoforms are localized at different subcellular compartments in both adipocytes and cancer cells. In this review, we highlight the unique roles of each Akt isoform by introducing published data obtained from both in vitro and in vivo studies. We also discuss the significant potential of the Akt isoforms as effective anticancer therapeutic targets.

Among the cell cycle-related mammalian cyclins, cyclin D1 is more closely connected with cell proliferation in response to extracellular signals than the cell cycle clock itself. Because both its mRNA and protein are labile, the intracellular abundance of cyclin D1 is thought to be largely regulated at the level of transcription. However, recent findings suggest that, in certain cell types, cyclin D1 is post-translationally regulated, and a disturbance of this regulatory mechanism induces aberrant entry into the cell cycle and proliferation, sometimes leading to diseases such as cancer. In this review, we summarize recent findings and discuss the physiological role and cellular function of the novel mechanism of regulation of cyclin D1 in terms of the control of cell proliferation.

The ceramide synthase (CerS) gene family comprises a group of highly conserved transmembrane proteins, which are found in all studied eukaryotes. The key feature of the CerS proteins is their role in ceramide synthase activity. Therefore, their original name ‘longevity assurance gene ( Lass ) homologs’, after the founding member, the yeast longevity assurance gene lag1 , was altered to ‘ CerS ’. All CerS have high sequence similarity in a domain called LAG1 motif and a subset of CerS proteins is predicted to contain a Homeobox (Hox) domain. These domains could be the key to the multiple roles CerS have. CerS proteins play a role in diverse biological processes such as proliferation, differentiation, apoptosis, stress response, cancer, and neurodegeneration. In this review, we focus on CerS structure and biological function with emphasis of biological functions in the widely used model systems Caenorhabditis elegans and Drosophila melanogaster . Also, we focus on the accumulating data suggesting a role for CerS in lipid homeostasis.

Centrosomes and cilia are critical eukaryotic organelles which have been in the spotlight in recent years given their implication in a myriad of cellular and developmental processes. Despite their recognized importance and intense study, there are still many open questions about their biogenesis and function. In the present article, we review the existing data concerning members of the tubulin folding pathway and related proteins, which have been identified at centrosomes and cilia and were shown to have unexpected roles in these structures.