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Intracellular Mediators (intracellular + mediator)

Distribution by Scientific Domains

Life Sciences	70%
Medical Sciences	30%

Selected Abstracts

Chondrocyte-specific Smad4 gene conditional knockout results in hearing loss and inner ear malformation in mice

DEVELOPMENTAL DYNAMICS, Issue 8 2009
Shi-Ming Yang
Abstract Smad4 is the central intracellular mediator of transforming growth factor-, (TGF-,) signaling, which plays crucial roles in tissue regeneration, cell differentiation, embryonic development, and regulation of the immune system. Conventional Smad4 gene knockout results in embryonic lethality, precluding its use in studies of the role of Smad4 in inner ear development. We used chondrocyte-specific Smad4 knockout mice (Smad4Co/Co) to investigate the function of Smad4 in inner ear development. Smad4Co/Co mice were characterized by a smaller cochlear volume, bone malformation, and abnormalities of the osseous spiral lamina and basilar membrane. The development of the hair cells was also abnormal, as evidenced by the disorganized stereocilia and reduced density of the neuronal processes beneath the hair cells. Auditory function tests revealed the homozygous Smad4Co/Co mice suffered from severe sensorineural hearing loss. Our results suggest that Smad4 is required for inner ear development and normal auditory function in mammals. Developmental Dynamics, 2009. © 2009 Wiley-Liss, Inc. [source]

MicroRNA in the immune system, microRNA as an immune system

IMMUNOLOGY, Issue 3 2009
Li-Fan Lu
Summary The advent of microRNA has potentially uncovered a new level of complexity to be considered for every biological process. Through the modulation of transcription and translation, microRNA alter the basal state of cells and the outcome of stimulatory events. The exact effect of the microRNA network and individual microRNA on cellular processes is only just starting to be dissected. In the immune system, microRNA appear to have a key role in the early differentiation and effector differentiation of B cells. In T cells, microRNA have been shown to be key regulators of the lineage induction pathways, and to have a strong role in the induction, function and maintenance of the regulatory T-cell lineage. MicroRNA are also important for regulating the differentiation of dendritic cells and macrophages via toll-like receptors, with responsibilities in suppressing effector function before activation and enhancing function after stimulation. In addition to regulating key processes in the immune system, microRNA may also represent an archaic immune system themselves. Small interfering RNA of viral origin has been shown to function as an intracellular mediator in the suppression of viral infection in eukaryotes as diverse as plants, insects, nematodes and fungi, and there is growing evidence that endogenous mammalian microRNA can have similar impacts. In this article we speculate that the anti-viral function of microRNA drove the expression of different subsets of microRNA in different cellular lineages, which may have, in turn, led to the myriad of roles microRNA play in lineage differentiation and stability. [source]

Novel Mechanisms for Feedback Regulation of Phospholipase C-, Activity

IUBMB LIFE, Issue 5 2002
Irene Litosch
Abstract The receptor-regulated phospholipase C- ,(PLC- ,) signaling pathway is an important component in a network of signaling cascades that regulate cell function. PLC- ,signaling has been implicated in the regulation of cardiovascular function and neuronal plasticity. The G q family of G proteins mediate receptor stimulation of PLC- ,activity at the plasma membrane. Mitogens stimulate the activity of a nuclear pool of PLC- ,. Stimulation of PLC- ,activity results in the rapid hydrolysis of phosphatidylinositol-4,5-bisphosphate, with production of inositol-1,4,5-trisphosphate and diacylglycerol, intracellular mediators that increase intracellular Ca 2+ levels and activate protein kinase C activity, respectively. Diacylglycerol kinase converts diacylglycerol to phosphatidic acid, a newly emerging intracellular mediator of hormone action that targets a number of signaling proteins. Activation of the G q linked PLC- ,signaling pathway can also generate additional signaling lipids, including phosphatidylinositol-3-phosphate and phosphatidylinositol-3,4,5-trisphosphate, which regulate the activity and/or localization of a number of proteins. Novel feedback mechanisms, directed at the level of G q and PLC- ,, have been identified. PLC- ,and regulators of G protein signaling (RGS) function as GTPase-activating proteins on G q to control the amplitude and duration of stimulation. Protein kinases phosphorylate and regulate the activation of specific PLC- ,isoforms. Phosphatidic acid regulates PLC- ,1 activity and stimulation of PLC- ,1 activity by G proteins. These feedback mechanisms coordinate receptor signaling and cell activation. Feedback mechanisms constitute possible targets for pharmacological intervention in the treatment of disease. [source]

Increasingly complex: New players enter the Wnt signaling network

BIOESSAYS, Issue 10 2002
Petra Pandur
Wnt proteins can activate different intracellular signaling cascades in various organisms by interacting with receptors of the Frizzled family. The first identified Wnt signaling pathway, the Wnt/,-catenin pathway, has been studied in much detail and is highly conserved among species. As to non-canonical Wnt pathways, the current situation is more nebulous partly because the intracellular mediators of this pathway are not yet fully understood and, in some cases, even identified. However, there are increasing data that prove the existence of non-canonical Wnt signaling and demonstrate its involvement in different developmental processes. In vertebrates, Wnt-11 and Wnt-5A can activate the Wnt/JNK pathway, which resembles the planar cell polarity pathway in Drosophila. The Wnt/Ca2+ -pathway has only been described in Xenopus and zebrafish so far and it is unclear whether it also exists in other organisms. Two recent papers provide us with new insight into non-canonical Wnt signaling by (1) presenting a new intracellular mediator of non-canonical signaling in Xenopus1 and (2) implicating the existence of an additional non-canonical Wnt signaling pathway in flies.2 BioEssays 24:881,884, 2002. © 2002 Wiley Periodicals, Inc. [source]

PRECLINICAL STUDY: FULL ARTICLE: Ethanol-induced activation of AKT and DARPP-32 in the mouse striatum mediated by opioid receptors

ADDICTION BIOLOGY, Issue 3 2010
Karl Björk
ABSTRACT The reinforcing properties of ethanol are in part attributed to interactions between opioid and dopaminergic signaling pathways, but intracellular mediators of such interactions are poorly understood. Here we report that an acute ethanol challenge induces a robust phosphorylation of two key signal transduction kinases, AKT and DARPP-32, in the striatum of mice. Ethanol-induced AKT phosphorylation was blocked by the opioid receptor antagonist naltrexone but unaffected by blockade of dopamine D2 receptors via sulpiride. In contrast, DARPP-32 phosphorylation was abolished by both antagonists. These data suggest that ethanol acts via two distinct but potentially synergistic striatal signaling cascades. One of these is D2-dependent, while the other is not. These findings illustrate that pharmacology of ethanol reward is likely more complex than that for other addictive drugs. [source]

Novel Mechanisms for Feedback Regulation of Phospholipase C-, Activity

Adapter protein CRKII signaling is involved in the rat pancreatic acini response to reactive oxygen species

JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2006
Alberto G. Andreolotti
Abstract Recent studies demonstrate that reactive oxygen species (ROS) are important mediators of acute pancreatitis, whether induced experimentally or in necrotizing pancreatitis in humans; however, the cellular processes involved remain unclear. Adapter protein CrkII, plays a central role for convergence of cellular signals from different stimuli. Cholecystokinin (CCK), which induces pancreatitis, stimulates CrkII tyrosine phosphorylation and CrkII protein complexes, raising the possibility it can be important in the acinar cell responses to ROS. Therefore, our aim was to investigate whether CrkII signaling is involved in the biological response of rat pancreatic acini to H2O2 and the intracellular mediators implicated. Treatment of isolated rat pancreatic acini with H2O2 rapidly stimulates CrkII phosphorylation, measured as electrophoretic mobility shift and by using a phosphospecific antibody (pTyr221). Tyrosine kinase blocker B44 inhibits the higher phosphorylation state, demonstrating that it occurs mainly in tyrosine residues. H2O2 -induced CrkII phosphorylation is time- and concentration-dependent, showing maximal effect with 3 mM H2O2 at 5 min. The intracellular pathways induced by H2O2 leading to CrkII tyrosine phosphorylation do not involve PKC, intracellular calcium, PI3-K or the actin cytoskeleton integrity. ROS generation clearly promotes the formation of protein complex CrkII,PYK2. In conclusion, ROS clearly affect the key adapter protein CrkII signaling by two ways: stimulation of CkII phosphorylation and a functional consequence: formation of CrkII,protein complexes. Because of its central role in activating more distal pathways, CrkII might likely play an important role in the ability of ROS to induce pancreatic cellular injury and pancreatitis. J. Cell. Biochem. © 2005 Wiley-Liss, Inc. [source]

Apoptosis: mechanisms and clinical implications

ANAESTHESIA, Issue 11 2000
P. C. A. Kam
The balance between cell survival and death is under tight genetic control. A multiplicity of extracellular signals and intracellular mediators is involved in maintaining this balance. When the cell is exposed to physical, biochemical or biological injury, or deprived of necessary substances, it activates a series of stress-response genes. With minimal insults, the cell may recover. With greater insults, single cell death, or apoptosis, results; the cell dies and is recycled to its neighbours. If the insult overwhelms a large number of cells then necrosis ensues, with an accompanying inflammatory response. Dysregulation of the controlling mechanisms of this system results in disease. Deficient apoptosis is associated with cancer, auto-immunity and viral infections. Excessive apoptosis is associated with ischaemic heart disease, stroke, neurodegenerative disease, sepsis and multiple organ dysfunction syndrome. There are myriad therapeutic options unfolding as understanding is gained of apoptosis and its control. [source]

Interleukin-1, and tumor necrosis factor , inhibit chondrogenesis by human mesenchymal stem cells through NF-,B,dependent pathways,

ARTHRITIS & RHEUMATISM, Issue 3 2009
N. Wehling
Objective The differentiation of mesenchymal stem cells (MSCs) into chondrocytes provides an attractive basis for the repair and regeneration of articular cartilage. Under clinical conditions, chondrogenesis will often need to occur in the presence of mediators of inflammation produced in response to injury or disease. The purpose of this study was to examine the effects of 2 important inflammatory cytokines, interleukin-1, (IL-1,) and tumor necrosis factor , (TNF,), on the chondrogenic behavior of human MSCs. Methods Aggregate cultures of MSCs recovered from the femoral intermedullary canal were used. Chondrogenesis was assessed by the expression of relevant transcripts by quantitative reverse transcription,polymerase chain reaction analysis and examination of aggregates by histologic and immunohistochemical analyses. The possible involvement of NF-,B in mediating the effects of IL-1, was examined by delivering a luciferase reporter construct and a dominant-negative inhibitor of NF-,B (suppressor-repressor form of I,B [srI,B]) with adenovirus vectors. Results Both IL-1, and TNF, inhibited chondrogenesis in a dose-dependent manner. This was associated with a marked activation of NF-,B. Delivery of srI,B abrogated the activation of NF-,B and rescued the chondrogenic response. Although expression of type X collagen followed this pattern, other markers of hypertrophic differentiation responded differently. Matrix metalloproteinase 13 was induced by IL-1, in a NF-,B,dependent manner. Alkaline phosphatase activity, in contrast, was inhibited by IL-1, regardless of srI,B delivery. Conclusion Cell-based repair of lesions in articular cartilage will be compromised in inflamed joints. Strategies for enabling repair under these conditions include the use of specific antagonists of individual pyrogens, such as IL-1, and TNF,, or the targeting of important intracellular mediators, such as NF-,B. [source]