Ernst Schering Foundation symposium proceedings最新文献

In recent years, there has been a growing realization that a static two-dimensional model of gene activation by transcription factors is inadequate. Based on the work from a number of groups (Kang et al. 2002; Liu and Bagchi 2004; Metivier et al. 2003; Park et al. 2005; Reid et al. 2003; Shang et al. 2000; Sharma and Fondell 2002; Vaisanen et al. 2005), it is becoming clear that transcriptional regulation by nuclear receptors is a dynamic and cyclical process (Metivier et al. 2006). There are significant consequences that arise from this shift in understanding, from nuclear receptors as ligand activated factors that bind to a response element to activate expression of a target gene to a process where the receptor repeatedly binds in order to achieve transcription. New insights that arise from viewing the activation process as cyclical and the consequences of this for developing new strategies that modulate the activity of the estrogen receptor are outlined in this chapter.

Mounting evidence indicates that human cancers may originate from malignant transformation of stem cells. The most convincing proof is found in acute myeloid leukemia, where only a small subset of slowly dividing cells was able to induce transplantable acute myeloid leukemia. Normal hematopoietic stem cells (HSC) are characterized by their unlimited ability to self-renew, give rise to a multitude of cells that exhibit more differentiated features, and show slow division kinetics. Using human HSC and mesenchymal stromal cells (MSC) as models, we and others have demonstrated the vital role of the cellular niche in maintaining the self-renewing capacity, that is, "stemness" of HSC. Without direct contact with the cellular niche, HSC tend to differentiate and lose their stemness. Similar to their normal counterparts, leukemia stem cells divide slowly and maintain their self-renewal capacity through interaction with the niche. As a consequence, they are resistant to conventional chemotherapy strategies that target rapidly dividing cells. Thus it is of utmost importance to understand the interaction between cellular niche and normal HSC as well as between leukemia stem cells and the niche to provide a basis for more efficient treatment strategies.

An important issue in cancer therapy is the presence of a population that is resistant to anticancer treatment. This resistance has been partly ascribed to the presence of quiescent stem cells in a cancer population. However, how the quiescent state is induced in a proliferating cancer population is totally obscure. We think that our study on the stem cell system of pigment cells will provide some insight into the molecular basis for cancer stem cells, because the quiescent melanocyte stem cell would be the ideal model for understanding the process generating quiescent stem cells. In this article, we review our latest understanding of the quiescent stem cells of the melanocyte lineage by referring to some related topics of cancer stem cells.

Inflammation is a physiological response that may go uncontrolled and thereby develop in a chronic way. This seems to happen in many common diseases of autoimmune, degenerative, or allergic character. Rheumatoid arthritis (RA) is by definition a chronic disease with an autoimmune inflammatory attack on diarthrodial cartilaginous joints. The development of new treatment neutralizing cytokines involved in the inflammatory attack has given relief and gives the promise of more effective treatment of already established disease. It is now time to set our eyes on a new vision to develop preventive and curative treatment based on knowledge of the unique and causative pathogenic mechanisms. To do this we believe it is important to identify the natural-selected polymorphisms that are associated with disease. These have proven to be extremely difficult to identify in complex diseases such as RA, but using animal models, this work is closer to reality. Animal models have recently been developed mimicking various aspects of the human disease. We will present an example in which a genetic polymorphism associated with the development of arthritis has been identified. On the basis of this finding, a new pathway involving control of immune tolerance by reactive oxidative species has been identified and a new class of antiinflammatory agents activating the induced oxidative burst protein complex is suggested.

The true potential of microprocess technology for process intensification is not yet fully clear and needs to be actively explored, although more and more industrial case stories provide information. This paper uses a shortcut cost analysis to show the major cost portions for processes conducted by microstructured reactors. This leads to predicting novel chemical protocol conditions, which are tailored for microprocess technology and which are expected to highly intensify chemical processes. Some generic rules to approach this are termed new process windows, because they constitute a new approach to enabling chemistry. Using such process intensification together with scaled-out microstructured reactors, which is demonstrated by the example of gas-liquid microprocessing, paves the road to viable industrial microflow processes. Several such commercially oriented case studies are given. Without the use of new process windows conditions, microprocess technology will probably stick to niche applications.

Drug discovery has successfully exploited the superfamily of seven transmembrane receptors (7TMR), with over 35% of clinically marketed drugs targeting them. However, it is clear that there remains an undefined potential within this protein family for successful drugs of the future. The human genome sequencing project identified approximately 720 genes that belong to the 7TMR superfamily. Around half of these genes encode sensory receptors, while the other half are potential drug targets. Natural ligands have been identified for approximately 215 of these, leaving 155 receptors classified as orphan 7TMRs having no known ligand. Deorphanisation of these receptors by identification of natural ligands has been the traditional method enabling target validation by use of these ligands as tools to define biological relevance and disease association. Such ligands have been paired with their cognate receptor experimentally by screening of small molecule and peptide ligands, reverse pharmacology and the use of bioinformatics to predict candidate ligands. In this manuscript, we review the methodologies developed for the identification of ligands at orphan 7TMRs and exemplify these with case studies.

G-protein-coupled receptors encoded by herpesviruses such as EBV, HCMV and KSHV are very interesting illustrations of the (patho)physiological importance of constitutive GPCR activity. These viral proteins are expressed on the cell surface of infected cells and often constitutively activate a variety of G-proteins. For some virus-encoded GPCRs, the constitutive activity has been shown to occur in vivo, i.e., in infected cells. In this paper, we will review the occurrence of virus-encoded GPCRs and describe their known signaling properties. Moreover, we will also review the efforts, directed towards the discovery of small molecule antagonist, that so far have been mainly focused on the HCMV-encoded GPCR US28. This virus-encoded receptor might be involved in cardiovascular diseases and cancer and seems an interesting target for drug intervention.

Many GPCR models have been built over the years for many different purposes, of which drug-design undoubtedly has been the most frequent one. The release of the structure of bovine rhodopsin in August 2000 enabled us to analyze models built before that period to learn things for the models we build today. We conclude that the GPCR modeling field is riddled with "common knowledge". Several characteristics of the bovine rhodopsin structure came as a big surprise, and had obviously not been predicted, which led to large errors in the models. Some of these surprises, however, could have been predicted if the modelers had more rigidly stuck to the rule that holds for all models, namely that a model should explain all experimental facts, and not just those facts that agree with the modeler's preconceptions.

Mutations leading to overexpression and activation of the oncogenes Myc and Ras are among the most frequent lesions known to occur in human and murine cancers. These genes are also the pioneering example for oncogene cooperation during tumorigenesis, whereby the anticancer effects of Myc deregulation (apoptosis) and oncogenic Ras (senescence) are antagonized and therefore canceled out by each other. Here I review the role of endogenous and overexpressed c-Myc in murine skin, focusing primarily on epidermal stem cells. In addition, recent data suggesting an essential role for the endogenous c-Myc-p21(CIP1) pathway in Ras-driven skin tumorigenesis are discussed.

It has now been over 10 years since Jan-Ake Gustafsson revealed the existence of a second form of the estrogen receptor (ERbeta) at a 1996 Keystone Symposium. Since then, substantial success has been made in distinguishing its potential biological functions from the previously known form (now called ERalpha) and how it might be exploited as a drug target. Subtype selective agonists have been particularly useful in this regard and suggest that ERbeta agonists may be useful for a variety of clinical applications without triggering classic estrogenic side effects such as uterine stimulation. These applications include inflammatory bowel disease, rheumatoid arthritis, endometriosis, and sepsis. This manuscript will summarize illustrative data for three ERbeta selective agonists, ERB-041, WAY-202196, and WAY-200070.