Showing papers in "Signal Transduction in 2006"
TL;DR: The non-modified PEI reagent was used to optimize transfection protocols for different cell-lines and was able to transiently transfect a number of cell- lines up to 40–90%.
Abstract: In search for a cheap and effective transfection reagent we used the positively charged polyplex-forming compound polyethylenimine (PEI). This compound is commercially available from different companies either as a non-modified chemical reagent or with additives as a more cost intensive transfection reagent. Here we used the non-modified PEI reagent to optimize transfection protocols for different cell-lines. With these optimized conditions we were able to transiently transfect a number of cell-lines up to 40–90%.
159 citations
TL;DR: This review discusses specific inhibition of IL-6-trans-signaling processes by a naturally occurring soluble form of gp130, demonstrating that this protein may emerge as an important future therapeutic in clinical applications for chronic inflammation.
Abstract: The cytokine interleukin-6 has been identified and cloned among others as B-cell stimulatory factor, hepatocyte stimulating factor, plasmacytoma growth factor, and interferon beta-2 Consequently, it emerged, that IL-6 controls a huge variety of cellular functions, among them induction of the acute phase response in the liver, mediation of inflammation and malignant transformation In this review, we summarize the so called classical IL-6 signaling, which is mediated by the complex of IL-6, the membrane bound IL-6R and two gp130 molecules, and an alternative pathway called trans-signaling, which apparently contributes to the development of chronic inflammation and cancer During trans-signaling an agonistic soluble IL-6R is generated, which sensitizes cells lacking the membrane bound IL-6R Finally, we discuss specific inhibition of IL-6-trans-signaling processes by a naturally occurring soluble form of gp130, demonstrating that this protein may emerge as an important future therapeutic in clinical applications for chronic inflammation
47 citations
TL;DR: The long held view of biological lipids acting as passive building blocks in biological membranes has now been superseded by the notion that the structure and composition of the membrane plays a crucial role in the regulation of protein function and numerous other biological processes.
Abstract: The long held view of biological lipids acting as passive building blocks in biological membranes has now been superseded by the notion that the structure and composition of the membrane plays a crucial role in the regulation of protein function and numerous other biological processes. This may be the result of specific protein-lipid recognition phenomena or alternatively regulation by sensing properties of the membrane such as the stored curvature elastic stress with the latter being the focus of the review.
33 citations
TL;DR: Depending on the scientific question and the time course of events, different experimental platforms are available to provide conditions of altered gravitational stimulation on ground and to prepare space experiments i.e. under real microgravity conditions.
Abstract: Scientists and technicians have been innovative in order to find experimental approaches to study the influence of gravity. Depending on the scientific question and the time course of events which are under investigation, different experimental platforms are available to provide conditions of altered gravitational stimulation on ground and to prepare space experiments i.e. under real microgravity conditions. The application profile ranges from studies with molecules or single cells up to humans.
31 citations
TL;DR: Experimental data from experiments on ground and in space reveal that especially the early phases ofgravity sensing share common features, and Cytoskeletal elements have been shown to play a master role in the complex processes of gravity sensing and graviorientation.
Abstract: Gravity sensing, gravity-dependent signalling pathways and resulting graviresponses are found even in single cells as shown in studies on unicellular animal and plant model systems. Although the gravity-dependent responses of single-celled systems are obviously very different, the presented experimental data from experiments on ground and in space reveal that especially the early phases of gravity sensing share common features. The gravisensory processes can be reduced to two principles: perception via intracellular statoliths and via the whole protoplast. Gravisensory ion channels and cascades of ubiquitous second messengers are proposed in most gravity-dependent signalling pathways and have been identified in some cases. Cytoskeletal elements have been shown to play a master role in the complex processes of gravity sensing and graviorientation. Research on ground has been complemented with experiments in microgravity, which greatly contributed to our understanding of gravi-related signalling processes.
24 citations
TL;DR: Investigations indicate the presence of an active, physiological graviperception mechanism in the flagellate gravitaxis, in some cases supported by a passive mechanism.
Abstract: Many photosynthetic or heterotrophic flagellates, from various taxa, show positive, negative and, in some cases, transversal gravitaxis. Most flagellates are unicellular; however, they can form aggregates or colonies. Two species have been studied in more detail, Chlamydomonas and Euglena, which can serve as model systems. Earlier theories suggested that gravitaxis is caused by a buoy effect: The cell is tail-heavy, and the propelling flagellum (flagella), inserting at the anterior end, pulls the organism upwards. Recent investigations, however, falsify these hypotheses and indicate the presence of an active, physiological graviperception mechanism, in some cases supported by a passive mechanism. In the photosynthetic Euglena, the cell body is heavier (1.04 g/mL) than the surrounding medium (water) and is assumed to exert pressure onto the lower membrane. The resulting force is believed to trigger mechano-sensitive calcium-specific ion channels. The molecular sensory transduction chain starts with the Ca influx which causes a depolarization of the membrane potential. The calcium is believed to bind to calmodulin which in turn activates an adenylyl cyclase. The produced cAMP is a secondary messenger and finally activates the flagellum reorientation. In Chlamydomonas, a mutant with defective mechano-sensitive channels was found which is agravitactic, indicating that also in this flagellate gravitaxis is mediated by an active physiological receptor.
24 citations
TL;DR: The special features of the various flight opportunities, which are made available by DLR for life sciences research, are described in some detail and other contributions will focus on the results obtained, especially in the area of gravity signal transduction.
Abstract: Investigations on the effects of gravity on living systems, especially the perception and transduction of this important environmental parameter, are in the focus of the German Space Life Sciences Program since several years. This program is managed – like all other space activities – by the German Aerospace Center DLR in its role as the German Space Agency. Funding of scientists, placing contracts to industry for the development of necessary space research facilities, and providing flight opportunities for performing space experiments including international coordination with other space agencies are the main responsibilities of the agency. In the present contribution the special features of the various flight opportunities, which are made available by DLR for life sciences research, are described in some detail. By this, scientists should become aware of the interesting possibilities to perform space research in the frame of the German Space Life Sciences Program, while other contributions in this special publications will focus on the results obtained, especially in the area of gravity signal transduction.
22 citations
TL;DR: The available data appear to support the potential of MAPK inhibition as a novel intervention strategy in renal disease, but future clinical studies are needed to substantiate this assumption, and to establish its safety.
Abstract: Mitogen activated protein kinases (MAPKs) are intracellular signal transduction molecules, which connect cell-surface receptor signals to intracellular processes. MAPKs regulate a range of cellular activities including cell proliferation, gene expression, apoptosis, cell differentiation and cytokine production. The MAPK superfamily consists of at least four families: extracellular signal-regulated kinase (ERK), p38 MAPK, Jun-NH2-terminal kinase (JNK), and ERK5. Each of these families exerts particular downstream effects, although interactions have been described. MAPK activity is present in the normal kidney. Moreover, in various types of renal disease, renal MAPK expression is increased. Interventions that provide renoprotection, such as ACE-inhibition or statin therapy, may reduce renal MAPK expression, suggesting that increased renal MAPK expression is involved in the pathophysiology of renal damage. Studies using specific MAPK inhibitors have been used to further elucidate this role. This review gives an overview of available in vitro data on MAPK activation (focussed on renal cell types), and describes MAPK localization and possible functions in the normal and diseased kidney in man, and in experimental renal disease. Studies reporting the effect of conventional renoprotective intervention on renal MAPK expression are reviewed, as well as the available data on specific MAPK inhibition, both in the clinical and experimental setting. The available data appear to support the potential of MAPK inhibition as a novel intervention strategy in renal disease, but future clinical studies are needed to substantiate this assumption, and to establish its safety. (copyright) 2006 Wiley-VCH Verlag GmbH & Co. KGaA
19 citations
TL;DR: This review focuses on the differential BMP signaling pathways initiated at distinct oligomerized signaling complexes as well as on the pathological aspects of B MP signaling in diseases and their potential for tissue regeneration.
Abstract: Bone morphogenetic proteins (BMPs) are multi-functional growth factors belonging to the transforming growth factor β (TGFβ) superfamily. BMPs are expressed in a large variety of tissues and organs, where they exhibit pleiotropic functions during development as well as in the adult organism. Thus maintenance of the BMP signaling pathways requires strict control and regulation by antagonists, co-receptors and inhibitors. BMPs exert their signals by binding to hetero-oligomeric signaling complexes composed of type I and type II receptors with serine/threonine kinase activity. They play a decisive role in the development of several diseases but are also involved in self-renewal of stem cells and tissue regeneration. These insights may lead to the design of future therapeutic treatments. This review focuses on the differential BMP signaling pathways initiated at distinct oligomerized signaling complexes as well as on the pathological aspects of BMP signaling in diseases and their potential for tissue regeneration.
16 citations
TL;DR: The data suggest that Blimp-1 is physiologically expressed in T lymphocytes during late stages of differentiation, induces down regulation of IL-2 production and a shortened life span and might thus contribute to a limitation of T cell immune responses.
Abstract: The transcriptional repressor Blimp-1 regulates terminal differentiation of B-lymphocytes and myeloid cells. We now show that Blimp-1 is also expressed in human and murine primary T lymphocytes. Blimp-1 expression is highest in freshly isolated primary T cells with an antigen experienced phenotype. Th2 and CD4+CD25+ cells exhibited higher levels of Blimp-1 mRNA than Th1 cells. However, ectopic expression of Blimp-1 by retroviral transduction neither altered the frequency of IFN-γ or IL-4 producing cells nor did it induce suppressor activity. In non-polarized cells, retroviral transduction of Blimp-1 led to a marked reduction in IL-2 secretion, to an inability to proliferate and to reduced viability. Our data suggest that Blimp-1 is physiologically expressed in T lymphocytes during late stages of differentiation, induces down regulation of IL-2 production and a shortened life span and might thus contribute to a limitation of T cell immune responses.
15 citations
TL;DR: The results suggest that another signal transduction chain, initiated by mechanical impedance to the root apex, interacts with the early stages of the gravitropism cascade and the effects of ethylene on grav itropism could be mediated by the mechanical impedance sensing and response systems.
Abstract: Gravitropism in roots involves at least three signal transduction chains. The first signal transduction chain is sub-cellular and operates within the gravity-perceiving cells in the root apex. The output of this perception system feeds into a second intercellular signal transduction chain (widely considered to involve auxin movement) that links events in the apical regions with the third signal transduction chain that controls cell expansion in the elongating cells. The present study probes the disputed role of ethylene in gravitropism by seeking to identify which parts of the gravitropism cascade are influenced by ethylene action. The results suggest that another signal transduction chain, initiated by mechanical impedance to the root apex, interacts with the early stages of the gravitropism cascade and the effects of ethylene on gravitropism could be mediated by the mechanical impedance sensing and response systems.
TL;DR: The core technologies of chemical genetics, diversity oriented synthesis, high-throughput screening and microarray technologies have recently been used in various combinations to shed light on an impressive diversity of areas, including neural lipid and auxin signalling, membrane protein co-localisation, protein kinase engineering, and imaging signalling-related processes.
Abstract: Chemical intervention in biological systems is a field undergoing explosive growth, and a growing number of applications in signal transduction have evolved from the rich variety of small molecule and other chemical tools now available for selective modulation of cellular processes The key enabling factor for the majority of recent discoveries has been close collaboration between chemists and cell biologists, bringing together expertise in the development and application of novel and biologically-relevant chemistry and an understanding of where these techniques can be brought to bear for greatest effect The core technologies of chemical genetics, diversity oriented synthesis, high-throughput screening and microarray technologies have recently been used in various combinations to shed light on an impressive diversity of areas, including neural lipid and auxin signalling, membrane protein co-localisation, protein kinase engineering, and imaging signalling-related processes While further innovation is required to demonstrate the full potential for selective chemical intervention to complement and to a degree supersede pure genetic approaches, it will continue to stimulate ground-breaking research, in both chemistry and biology, for many years to come
TL;DR: Information is summarized about the Smad dependent and Smad independent TGF-β signaling network in hepatic stellate cells (HSCs) and hepatocytes, with emphasis on its role in chronic liver disease.
Abstract: Transforming growth factor (TGF)-β is a major mediator of fibrosis in diverse organs/tissues, including liver, due to its gene regulatory properties that lead to high expression and secretion of extracellular matrix components. Whereas the canonical Smad pathway seems to be very simple, TGF-β turns out to be a multiplicity factor with a highly cell type specific outcome and therefore, no universally valid plan of its signal transduction can be formulated. In the present review, we will summarize information about the Smad dependent and Smad independent TGF-β signaling network in hepatic stellate cells (HSCs) and hepatocytes, with emphasis on its role in chronic liver disease. In addition, current state of the art anti-TGF-β strategies for liver fibrosis treatment are discussed.
TL;DR: A comprehensive survey is provided on the application of a random positioning machine (RPM) for studies on gravitational effects on mammalian cells to elucidate three dominant cellular pathways that are affected by weightlessness.
Abstract: A comprehensive survey is provided on the application of a random positioning machine (RPM) for studies on gravitational effects on mammalian cells. The RPM is suitable to simulate microgravity conditions and allows performing a high number of on-ground experiments wherein mammalian cells are exposed to reduced gravity. Most of these experiments have been performed either to prove or extend observations made during spaceflights or to develop and prepare new spaceflight experiments. They did not only bring a tremendous number of observations, but they helped to elucidate three dominant cellular pathways that are affected by weightlessness. The apoptotic, the immune-activating and the bone differentiation pathways are discussed.
TL;DR: New data about the molecular mechanisms involved in the TGFβ-induced Smad-independent regulation of epithelial cell migration and actin cytoskeleton reorganisation of carcinoma cells are focused on.
Abstract: TGFβ, particularly TGFβ1-3, has been shown to promote epithelial dedifferentiation or epithelial-mesenchymal transition (EMT). While inhibition of epithelial cell proliferation in response to TGFβ is mainly mediated by the well-characterised Smad-pathway and subsequent regulation of gene transcription, the molecular mechanisms leading to TGFβ-induced migration, invasion and metastasis of epithelial tumour cells are less clear. Recent results from several groups suggest that the gain of tumourigenic activity by TGFβ includes signalling by mitogen-activated protein kinases (MAP kinases), phosphatidylinositol 3-kinase (PI3-K) and Rho-GTPases. Activation of the MAP kinases extracellular signal-regulated kinase (ERK) 1 and 2, p38 as well as c-jun N-terminal kinase (JNK) has been identified as important steps in TGFβ-induced, Smad4-independent signal transduction in epithelial cells. A role of activated ERK and JNK and their association with focal complexes in TGFβ-induced cell migration and actin cytoskeleton reorganisation of carcinoma cells has been identified recently. In this review we will focus on new data about the molecular mechanisms involved in the TGFβ-induced Smad-independent regulation of epithelial cell migration.
TL;DR: The main advantages and limitations of these tools are discussed in this paper, where specific examples are used to illustrate the application of liquid NMR, solid state NMR spectroscopy and electrospray ionisation mass spectrometry.
Abstract: Signalling lipids regulate cellular events directly by recruiting and/or activating specific proteins or indirectly by locally modifying the physical properties of the membrane. These events trigger the co-localisation and interaction of proteins on membranes. This in turn effects the function and the properties of the proteins. To enable a comprehensive study of the complex and spatially heterogeneous natural membrane, complementary analytical tools need to be applied. Spectroscopy tools such as nuclear magnetic resonance spectroscopy and mass spectrometry provide the sensitivity and the precision required for detecting low amounts of highly transient signalling lipids, but also determine their effect on membrane structure. Specific examples are used to illustrate the application of liquid NMR spectroscopy, solid state NMR spectroscopy and electrospray ionisation mass spectrometry. The main advantages and limitations of these tools are discussed in this review.
TL;DR: Initial research is presented on a novel technique for targeting combinatorial peptide aptamers to a protein binding-site using a small-molecule binding-partner (or ‘Trojan horse’).
Abstract: Peptide aptamers are powerful chemical genetic tools for the dissection of biological networks, but their application to in vivo systems has been limited by the challenging problem of targeting peptides to a specific site on a single target protein. Here we present our initial research on a novel technique for targeting combinatorial peptide aptamers to a protein binding-site using a small-molecule binding-partner (or ‘Trojan horse’). Novel peptide-based inhibitors for Plasmodium falciparum myristoyl-CoA:protein N-myristoyl transferase (PfNMT) have been selected from a one-bead one-compound library using a high-throughput on-bead screening methodology, targeted to the active site of NMT with a myristate (C14 : 0 fatty acid) substrate analogue. From an initial screen of an unbiased 130321-compound library of lipid/combinatorial peptide chimeras, we have selected 6-mer peptides in an on-bead assay which show NMT inhibition with IC50 values ranging down to low micromolar.
TL;DR: The potentiation of bradykinin action can occur by different mechanisms, depending on the system and the applied potentiating factor used, in some cases compared to own results.
Abstract: Potentiation of hormone actions can occur by different mechanisms, including inhibition of degrading enzymes, interaction with the hormone receptor leading to stabilization of bioactive conformation or leading to receptor homo- and hetero-oligomerization, receptor phosphorylation and dephosphorylation or can occur by directly influencing the signal transduction and ion channels. In this review the potentiation of bradykinin actions in different systems by certain compounds will be reviewed. Despite many long years of experimental research and investigation the mechanisms of potentiating action remain not fully understood. One of the most contradictory findings are the distinct differences between the inhibition of the angiotensin I-converting enzyme and the potentiation of the bradykinin induced smooth muscle reaction. Contradictory findings and hypothesized mechanisms in the literature are discussed in this review and in some cases compared to own results. Investigation of potentiating actions was extended from hypotension, smooth muscle reaction and cellular actions to activation of immunocompetent cells. In our opinion the potentiation of bradykinin action can occur by different mechanisms, depending on the system and the applied potentiating factor used.
TL;DR: The RRS is proposed as a valuable alternative interaction screening method that can widely be used among protein classes and that has been further developed by this group into a high-throughput screening system.
Abstract: The fast paced progress in genomics yielded a multitude of novel identified genes. Therefore reliable and up scalable methods are required to identify the functions of the encoded proteins. By using protein-protein interaction screening technologies, the function of many proteins has successfully been assigned, and proved in combination with other techniques. We describe the application of an in vivo screening system for protein-protein interactions, the Ras-recruitment system (RRS). The RRS has been used extensively to identify novel interaction partners, also in cases where common systems failed. Therefore we propose the RRS as a valuable alternative interaction screening method that can widely be used among protein classes and that has been further developed by our group into a high-throughput screening system.
TL;DR: New data suggest that CTLA-4 is also able to transmit positive signals for increased survival and might be involved in the generation of the memory compartment.
Abstract: The closely related members of the Ig-family of co-stimulators CD28 and CTLA-4 (CD152) show distinct functions regarding T cell activation but have also many features in common during T cell differentiation. Although CD28 and CTLA-4 share some of their intracellular binding partners, CD28 is the main activating co-stimulator of T cells while the role of CTLA-4 is to mainly down regulate T cell responses. Despite the well known function of CTLA-4 as a negative regulator of T cell function, new data suggest that CTLA-4 is also able to transmit positive signals for increased survival and might be involved in the generation of the memory compartment. The knowledge of how both molecules transmit their respective signals and how these signals are integrated during a T cell response is of importance for the understanding of T cell mediated immune responses and future therapeutic interventions in immune pathologies.
TL;DR: In this paper, the role of phospholipids, particularly the phosphoinositides (PIs), in the processes that regulate mast cell exocytosis is discussed.
Abstract: The release of pre-formed mediators such as histamine from mast cells and basophils is an integral part of the normal immune response to infection by parasites. This exocytosis is also characteristic response in a number of disease states including asthma, which, due to their prevalence in western society are becoming of increasing clinical importance. In an effort to tackle this growing problem much work has gone into unlocking the mechanisms through which mast cells function in health and disease. To date we have learned a lot about the various proteins that regulate degranulation. However, our knowledge on the contribution of lipids to this process is less clear. This review will discuss the role of phospholipids, particularly the phosphoinositides (PIs) in the processes that regulate mast cell exocytosis.
TL;DR: Data suggest that M1-facilitation of ACh release results mainly from activation of the IP3 pathway, which can be dissociated from the way M1 receptor operates suppression of neuromodulation through M2-inhibitory and A2A-facilitatory receptors, which might involve secondary PKC activation.
Abstract: Acetylcholine (ACh) facilitates its own release acting at muscarinic M1 receptors on rat motoneurons. While the M1 positive feedback mechanism is operative there is a concomitant suppression of the ability of muscarinic M2-inhibitory and adenosine A2A-facilitatory receptors to control [3H]ACh release. We aimed at investigating whether M1-occlusion of M2 and A2A receptors function could result from interplay at second messengers level. Drugs blocking the IP3 pathway, like LiCl and 2-aminoethoxydiphenylborane (2-APB), but not the selective PKC inhibitor, chelerythrine, attenuated M1 facilitation by McN-A-343. PKC activation with phorbol 12-myristate 13-acetate mimicked the ability of McN-A-343 to suppress M2-inhibition and A2A-facilitation of [3H]ACh release caused by oxotremorine and CGS 21680C, respectively. Co-application of chelerythrine together with McN-A-343 restored oxotremorine-inhibition and CGS 21680C-facilitation, but this was not observed when the M1 agonist was applied together with LiCl and 2-APB. McN-A-343 also masked facilitation of [3H]ACh release caused by stimulators of the cyclic AMP pathway, forskolin and rolipram. Data suggest that M1-facilitation of ACh release results mainly from activation of the IP3 pathway. This mechanism can be dissociated from the way M1 receptor operates suppression of neuromodulation through M2-inhibitory and A2A-facilitatory receptors, which might involve secondary PKC activation.
TL;DR: In this article, the effects of different gravity conditions on the retinal spreading depression (rSD) were investigated, which is an example of self organization and pattern formation in the central nervous system (CNS).
Abstract: The effects of different gravity conditions on the retinal Spreading Depression (rSD) were investigated. The rSD, an excitation depression wave in retinal tissue is used as an example of self organization and pattern formation in the central nervous system (CNS). The properties of such phenomena depend critically on the parameters of the system, small changes in the system can thus induce significant changes in the propagation properties of the SD. Gravity is a small but permanently stimulus on earth, absence of gravity and amplification respectively may have severe consequences for the function of the brain as an excitable medium. Microgravity experiments were performed on a TEXUS sounding rocket mission (5 min μg) and two DLR parabolic flight missions (20 s μg), hypergravity experiments were performed in the centrifuge in the lab. In this presentation we summarize the effects of altered gravity conditions on different parameters of the rSD. The results are discussed also in their relation to other earlier experiments with propagating action potentials under different gravity conditions. For both self organized biological systems a gravity dependence could be shown.
TL;DR: An estimation of the gravity impact on melanocyte function may be of importance to asses the risk of astronauts to develop pigmentary disorders, particularly melanoma and other relevant skin cancers, during long-term spaceflights.
Abstract: The human skin acts as a first barrier of defense to protect the internal organs from various chemical and physical environmental stress factors like solar ultraviolet radiation (UV) and mechanical stimuli. Human melanocytes (located strategically in the basal layer of the skin epidermis) represent a crucial protective barrier against UV irradiation and oxidative stress by generating the radical-scavenging pigment melanin. However, melanin is also known to act as a photosensitizer that generates active oxygen species upon UV irradiation, which may initiate pigmentary disorders like vitiligo due to loss of melanocytes as well as oncogenic melanocyte transformation. Melanocytes may further act as a protective immune barrier at the dermo-epidermal junction and thus participate in immune surveillance. For melanocytes it is known that the second messenger cyclic guanosine-3′,5′-monophosphate (cGMP) plays a key role in UVB-induced melanogenesis involving nitric oxide (NO) signaling. Moreover, cGMP is involved in NO-induced perturbation of melanocyte-extracellular matrix interactions that may lead to loss of melanocytes and support melanoma metastasis. In the frame of the current space exploration, investigations on the influence of altered gravity on melanocyte physiology are of special interest. As cGMP appears to play an important signaling role in melanocyte physiology, a brief overview is presented on the role of the guanylyl cyclase-cGMP signaling, with a focus on the melanocyte response to hypergravity. An estimation of the gravity impact on melanocyte function may be of importance to asses the risk of astronauts to develop pigmentary disorders, particularly melanoma and other relevant skin cancers, during long-term spaceflights.
TL;DR: Novel aspects in TGFβ signaling and transcription are focused on and recent advances in both cytoplasmic and nuclear crosstalk mechanisms between Smad and non-Smad signaling pathways are summarized and how this interaction results in the fine-tuning of Smad-mediated transcription during cancer progression is summarized.
Abstract: The multifunctional activities of transforming growth factor-beta (TGFβ) endow it with both tumor suppressor and tumor promoting activities, depending on the stage of carcinogenesis and the cellular activation state. In early tumor stages, TGFβ inhibits epithelial cell growth through induction of apoptosis and transcriptional regulation of cell cycle controlling genes. During tumor progression, however, many cancer cells escape from TGFβ-induced growth inhibition and, instead, respond to TGFβ with increased malignancy. TGFβ stimulates tumor promotion particularly in those tumor cells in which Smad-signaling remains functional and through transcriptional regulation of gene expression. Thus, loss of sensitivity to growth inhibition by TGFβ is not synonymous with complete loss of TGFβ signaling. Rather, it suggests that tumor cells gain advantage by selective inactivation of TGFβ tumor suppressor activities while retaining its tumor promoting functions. In this review we focus on novel aspects in TGFβ signaling and transcription and in particular on the role of Smad-interacting transcription factors. We also summarize recent advances in both cytoplasmic and nuclear crosstalk mechanisms between Smad and non-Smad signaling pathways and how this interaction results in the fine-tuning of Smad-mediated transcription during cancer progression. This knowledge will help to better understand the molecular mechanisms responsible for the switch of TGFβ from a tumor suppressor to a tumor promotor.
TL;DR: Three systems of increasing complexity are considered: the slime molds Physarum and Dictyostelium, which exhibit gravitaxis, the negative gravitropic sporangium of the zygomycete Phycomyces as a single cell structure with the fastest graviresponses known so far, and the fruit bodies of the basidiomycetes Coprinus and Flammulina as highly complex structures with the ability to generate positional information and
Abstract: The analysis of gravisensing in fungi has not yet proceeded as far as in other systems, such as sensory cells for maintenance of equilibrium in crustaceans and vertebrates, Chara rhizoids or plant roots with regard to positive gravitropism. However, considerable progress has recently been made with several fungal systems in the field of graviresponses. This particularly holds true for the molecular basis of primary events. In this review three systems of increasing complexity are considered: the slime molds Physarum and Dictyostelium, which exhibit gravitaxis, the negative gravitropic sporangium of the zygomycete Phycomyces as a single cell structure with the fastest graviresponses known so far, and the fruit bodies of the basidiomycetes Coprinus and Flammulina as highly complex structures with the ability to generate positional information and cell signalling in the context of negative gravitropism.
TL;DR: This work shows that ectopic expression of Blimp-1 is sufficient to induce an unfolded protein response (UPR), as evidenced by the generation of the processed form of XBP-1 and upregulation of the classical UPR target BIP, in both the B cell lymphoma cell line WEHI 231 and in mouse primary splenic B cells.
Abstract: Terminal differentiation of B cells into antibody secreting plasma cells is an essential step for eliciting a successful humoral immune response. The two transcription factors B lymphocyte-induced maturation protein-1 (Blimp-1) and X-box-binding protein-1 (XBP-1) are indispensable for this process. Hereby, XBP-1 activation depends on Blimp-1. However, it is not known if Blimp-1 alone, in the absence of differentiation signals, can induce XBP-1 processing. Here we show that ectopic expression of Blimp-1 is sufficient to induce an unfolded protein response (UPR), as evidenced by the generation of the processed form of XBP-1 and upregulation of the classical UPR target BIP, in both the B cell lymphoma cell line WEHI 231 and in mouse primary splenic B cells. Interestingly, the amino terminal part of Blimp-1 comprising amino acids 1-751 was sufficient to induce the above effects while the carboxy terminal part comprising amino acids 465-856 had no effect. Taken together our results identify Blimp-1 as the upstream molecule, capable of triggering the UPR in B cells resulting in XBP-1 processing, which is an important step during plasma cell generation.