Ernst Schering Foundation symposium proceedings最新文献

Postmenopausal women that still have an uterus and suffer from hot flushes are treated with combinations of estrogens and progestins. Whereas estrogens are indispensable for treating postmenopausal symptoms, progestins are added to counteract the proliferative activity of estrogens on uterine epithelial cells. However, in the mammary gland, progestins, given together with estrogens, stimulate the proliferation of mammary epithelial cells. Therefore, progestins with reduced proliferative activity in the mammary gland would be of advantage for hormone therapy of postmenopausal women. In order to identify progestins with better tissue-selectivity, we exploited the activation of different signal transduction pathways by the classical progesterone receptor. We demonstrated that progestins with reduced non-genomic versus genomic activity in vitro show a better dissociation of uterine versus mammary gland effects in vivo than medroxyprogesterone acetate (MPA), a synthetic progestin that is widely used in hormone therapy.

Normal proliferating cells and tumour cells in particular express the pyruvate kinase isoenzyme type M2 (M2-PK, PKM2). The quaternary structure of M2-PK determines whether the glucose carbons are degraded to pyruvate and lactate with production of energy (tetrameric form) or channelled into synthetic processes, debranching from glycolytic intermediates such as nucleic acid, amino acid and phospholipid synthesis. The tetramer:dimer ratio of M2-PK is regulated by metabolic intermediates, such as fructose 1,6-P2 and direct interaction with different oncoproteins, such as pp60v-src kinase, HPV-16 E7 and A-Raf. The metabolic function of the interaction between M2-PK and the HERC1 oncoprotein remains unknown. Thus, M2-PK is a meeting point for different oncogenes and metabolism. In tumour cells, the dimeric form of M2-PK is predominant and has therefore been termed Tumour M2-PK. Tumour M2-PK is released from tumours into the blood and from gastrointestinal tumours also into the stool of tumour patients. The quantification of Tumour M2-PK in EDTA plasma and stool is a tool for early detection of tumours and therapy control.

Mother Nature utilizes simple precursors to build up complex organic molecules efficiently. One important example is the C3 building block dihydroxyacetone phosphate, which is used in various enzyme-catalyzed reactions. Following this biosynthetic strategy the DHAP equivalent 'dioxanone' can be used in organocatalytic reactions to synthesize sugars, aminosugars, carbasugars, polyoxamic acids and sphingosines. In this respect, organocatalytic domino reactions can also be seen as biomimetic as they are reminiscent of tandem reactions that may occur during biosyntheses of complex natural products. In nature, the coenzyme thiamin (vitamin B1), a natural thiazolium salt, is used in biochemical nucleophilic acylations ('Umpolung'). The catalytic active species is a nucleophilic carbene. Mimicking this approach, organocatalytic carbene catalysis has emerged to an exceptionally fruitful research area, which is used in asymmetric C-C bond formations.

Leukocyte extravasation and entry into tissue forms the basis for inflammatory reactions and lymphocyte surveillance. After docking at the blood vessel wall at sites of exit leukocytes migrate through the endothelial cell layer and the underlying basement membrane, a process described as diapedesis. In recent years, several endothelial membrane proteins that which participate in this process have been identified. This review focuses on three membrane proteins located at endothelial cell contacts that are involved in the regulation of leukocyte diapedesis. The endothelial cell selective adhesion molecule (ESAM) at endothelial tight junctions and the vascular endothelial receptor-type protein tyrosine phosphatase (VE-PTP), a protein associating with VE-cadherin, both seem to control the integrity of endothelial cell contacts during diapedesis. CD99 and the distantly related CD99L2 are leukocyte membrane proteins that do not belong to any known protein family. They are expressed at endothelial cell contacts and participate in the migration of leukocytes through endothelium and basement membrane.

The progesterone receptor (PR) in cooperation with coregulator complexes coordinates crucial processes in female reproduction. To investigate the dynamic regulation of PR activity in vivo, a new transgenic mouse model utilizing a PR activity indicator (PRAI) system was generated. Studies utilizing the PRAI mouse have revealed that progesterone temporally regulates PR activity in female reproductive tissues. Specifically, progesterone rapidly enhances PR activity immediately after administration. However, chronic progesterone stimulation represses PR activity in female reproductive organs. Like progesterone, RU486 also temporally regulates PR activity in female reproductive organs. However, the temporal regulation of PR activity by RU486 is the inverse of progesterone's activity. RU486 acutely represses PR activity after injection but increases PR activity after chronic treatment in female reproductive tissues. Treatment with a mixed antagonist/agonist of PR, when compared to natural hormone, results in dramatically different tissue-specific patterns of intracellular PR activity, coregulator levels, and kinase activity. Transcriptional regulation of gene expression by PR is facilitated by coordinate interactions with the steroid receptor coactivators (SRCs). Bigenic PRAI-SRC knockout mouse models enabled us to draw a tissue-specific coactivator atlas for PR activity in vivo. Based on this atlas, we conclude that the endogenous physiological function of PR in distinct tissues is modulated by different SRCs. SRC-3 is the primary coactivator for PR in the breast and SRC-1 is the primary coactivator for PR in the uterus.

The mammary gland begins development during embryogenesis but after exposure to hormonal changes during puberty and pregnancy undergoes extensive further development. Hormonal changes are key regulators in the cycles of proliferation, differentiation, apoptosis and remodelling associated with pregnancy, lactation and involution following weaning. These developmental processes within the breast epithelium can be explained by the presence of a long-lived population of tissue-specific stem cells. The longevity of these stem cells makes them susceptible to accumulating genetic change and consequent transformation. The ovarian steroid progesterone, acting via the secreted factor Wnt4, is known to be essential for side branching of the mammary gland. One function of Wnt proteins is self-renewal of adult tissue stem cells, suggesting that progesterone may exert its effects within the breast, at least partly, by regulating the mammary stem cell population.

Organocatalysis, catalysis with low-molecular weight catalysts in which a metal is not part of the catalytic principle or the reaction substrate, can be as efficient and selective as metal- or biocatalysis. Important discoveries in this area include novel Lewis base-catalyzed enantioselective processes and, more recently, simple Brønsted acid organocatalysts that rival the efficiency of traditional metal-based asymmetric Lewis acid-catalysts. Contributions to organocatalysis from our laboratories include several new and broadly useful concepts such as enamine catalysis and asymmetric counteranion-directed catalysis. Our laboratory has discovered the proline-catalyzed direct asymmetric intermolecular aldol reaction and introduced several other organocatalytic reactions.

The design of catalytic reactions that proceed with high enantioselectivity is an important goal in organic synthesis. Increased interest in this research area has resulted in substantial progress, particularly in the field of metal catalyzed transformations. In recent years small organic molecules have been used as organocatalysts for a variety of enantioselective reactions. Among these, secondary amine catalysts are the most widely applied and can be used in the activation of the nucleophilic component through enamine formation (enamine catalysis), or by formation of an iminum intermediate to activate the electrophile (iminium catalysis). Additionally, chiral diols and thioureas, as well as carbene- and DMAP-derivatives (hydrogen bonding-, nucleophilic catalysis), have been shown to be versatile catalysts for enantioselective transformations. An alternative to these strategies is the activation of an electrophile or nucleophile by use of a chiral Brønsted acid. Compared to amino-, carbene-, pyridine- and hydrogen-bonding catalyzed transformations, enantioselective Brønsted acid catalysis has only recently emerged as important and promising area of research. In the course of our research program we were able to contribute significantly to the field of enantioselective Brønsted acid catalysis over the last 2 years, and could demonstrate for the first time that in various enantioselective transformations chiral Brønsted acid catalysts can give better or at least comparable results to metal-catalyzed processes. In this chapter we will highlight some of our most recent results and will, additionally, describe how we initially entered the field of asymmetric Brønsted acid catalysis by starting of from a biomimetic approach using nature as a role model.