Current Signal Transduction Therapy

ISSN: 1574-3624

Current Signal Transduction Therapy
Volume 2, Number 3, September 2007

Contents


The Role of IL-15 Signaling in the Induction of Innate Antiviral Responses Pp. 180-185
N. Gill, N.M. Lauzon and A.A. Ashkar
[Abstract]


A Clinical View of BDNF-TrkB Signaling in the Treatment of Major Depression Pp. 186-189
S.-J. Tsai
[Abstract]


Fluoride Interactions: From Molecules to Disease Pp. 190-213
A. Strunecka, J. Patocka, R.L. Blaylock and N.J. Chinoy
[Abstract]


The Role of Epithelial-Mesenchymal Interactions in Tissue Repair, Fibrogenesis and Carcinogenesis Pp. 214-220
D.V. Do, A. Mukhopadhyay, I.J. Lim and T.T. Phan
[Abstract]


Manipulation of Signal Transduction by Botulinum Neurotoxins and their Derivatives Pp. 221-225
J.A. Chaddock and K.A. Foster
[Abstract]


Redox Homeostasis, Bioactive Agents and Transduction Therapy Pp. 226-239
A. Blázovics
[Abstract]


Signal Transduction by the Cytoplasmic Domain of Neuregulin-1 and its Roles During Neuronal Aging Pp. 240-245
J. Bao
[Abstract]


The Phosphoinositide 3-Kinase (PI3K)/AKT Signaling Pathway as a Therapeutic Target for the Treatment of Human Acute Myeloid Leukemia (AML) Pp. 246-256
A.M. Martelli, G. Tabellini, R. Bortul, M. Nyåkern, P.L. Tazzari, C. Evangelisti and L. Cocco
[Abstract]




Abstracts


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The Role of IL-15 Signaling in the Induction of Innate Antiviral Responses
N. Gill, N.M. Lauzon and A.A. Ashkar

Innate immunity plays a critical role against viral infections, acting as the first line of defense against pathogens. Innate antiviral cytokines are induced early in protection and play a vital role in clearance of the infection and survival of the host. Interleukin 15 (IL-15) is a cytokine that has been implicated in the establishment of an antiviral state. It is part of the 4-alpha helix bundle family, and shares the IL-2Rβ and the common γchain for signaling. However the 1L-15Rα directs where IL-15 will bind and carry out its functions. IL-15Rα is present on antigen presenting cells (APCs) including dendritic cells (DCs) and macrophages and assists in their activation yet it is not required on the surface of all APCs. Certain APCs can bind IL-15 through the IL-15Rα and present it in trans to other cells that do not have the alpha receptor. Unlike other cytokines which can act at a distance from the site of secretion, IL-15 is more tightly regulated since cells must both express IL-15Rα and produce IL-15 in order to present it to other cells. IL-15 is one of the only cytokines that pre-exists in cells and is quickly released after viral infection; hence it is very important in the innate antiviral response. It assists in the initiation of an antiviral state by causing synthesis and secretion of IFNs, release of iNOS and activation, proliferation and differentiation of NK cells. In this review we will focus on IL-15 signaling and the results of this signaling on innate antiviral responses. An understanding of the IL-15 signaling pathway will prove important in the development of novel therapies inducing early innate responses against infections and contributing to overall protection.


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A Clinical View of BDNF-TrkB Signaling in the Treatment of Major Depression
S.-J. Tsai

Major depressive disorder is a common mental disease with unknown aetiology. Recent pre-clinical and clinical studies have suggested that the receptor tropomyosin related kinase B (TrkB) and its ligand, brain derived neurotrophic factor (BDNF), play essential roles in the pathogenesis and treatment of major depression. BDNF-TrkB pathway down-regulation may be the most important cause of major depression, while treatments that activate this pathway may improve depressive symptoms. Antidepressants, the main biological treatment for major depression, have been reported to increase central BDNF levels. However, a substantial proportion of depressed patients do not improve clinically despite appropriate antidepressant treatment and, in rare cases, antidepressants can induce or increase suicidal tendencies. In this report, several possible mechanisms relating to BDNF-TrkB signaling are proposed to account for these adverse effects of antidepressants. In addition, several strategies that may increase BDNF-TrkB signaling are proposed for the improved treatment of major depression.


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Fluoride Interactions: From Molecules to Disease
A. Strunecka, J. Patocka, R.L. Blaylock and N.J. Chinoy

Fluoride has long been known to influence the activity of various enzymes in vitro. Later it has been demonstrated that many effects primarily attributed to fluoride are caused by synergistic action of fluoride plus aluminum. Aluminofluoride complexes have been widely used as analogues of phosphate groups to study phosphoryl transfer reactions and heterotrimeric G proteins involvement. A number of reports on their use have appeared, with far-reaching consequences for our understanding of fundamental biological processes. Fluoride plus aluminum send false messages, which are amplified by processes of signal transduction. Many investigations of the long-term administration of fluoride to laboratory animals have demonstrated that fluoride and aluminofluoride complexes can elicit impairment of homeostasis, growth, development, cognition, and behavior. Ameliorative effects of calcium, vitamins C, D, and E have been reported. Numerous epidemiological, ecological, and clinical studies have shown the effects of fluoride on humans. Millions of people live in endemic fluorosis areas. A review of fluoride interactions from molecules to disease is necessary for a sound scientific assessment of health risks, which may be linked to the chronic intake of small doses of fluoride and aluminum from environmental and artificial sources.


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The Role of Epithelial-Mesenchymal Interactions in Tissue Repair, Fibrogenesis and Carcinogenesis
D.V. Do, A. Mukhopadhyay, I.J. Lim and T.T. Phan

The epithelium and the mesenchyme comprise the two important cellular partitions found in virtually every organ, and one influence the other via paracrine and cell-cell interactions. These epithelial-mesenchymal interactions have been shown to play important roles for normal tissue development during embryogenesis, and also exert crucial roles in the adult, being involved in roles as diverse as mammary gland development to skin homeostasis and repair. Studies have revealed that pathological disorders in these interactions may result in fibrogenesis and carcinogenesis, and a number of in vitro and in vivo models have been developed and employed to specifically investigate the epithelial-mesenchymal interactions in these scenarios. A thorough understanding of the roles of epithelial-mesenchymal interactions in tissue repair, fibrogenesis and carcinogenesis will facilitate and define the appropriate treatment for tissue fibrotic and carcinogenic states.


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Manipulation of Signal Transduction by Botulinum Neurotoxins and their Derivatives
J.A. Chaddock and K.A. Foster

Botulinum neurotoxins produced by various Clostridium sp are the most potent acute lethal toxins known, and yet they have found increasing use in the clinical treatment of diseases or conditions involving neuromuscular or autonomic neuronal transmission. By a process involving proteolytic cleavage of one or more SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, botulinum toxins inhibit the release of acetylcholine from peripheral cholinergic nerve terminals. Cleavage of SNARE proteins is both specific and effective, and leads to blockade of secretory vesicle fusion that is maintained for many weeks or months. Though inhibition of release of transmitter is currently the most clinically-relevant endpoint, SNARE proteolysis can also inhibit presentation of receptors, channels and other surface-membrane located materials. The implications for signal transduction are only just becoming apparent, but are an important facet of the mechanism of action of botulinum neurotoxins. Additionally, the ubiquitous distribution of the SNARE proteins ensures that proteolysis-dependent inhibition of transmitter release and receptor/channel presentation is theoretically not confined to neuronal targets.

This review will consider the potential of botulinum neurotoxins as inhibitors of intercellular communication, and highlight the general concept of deriving novel therapeutic molecules from the neurotoxins.


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Redox Homeostasis, Bioactive Agents and Transduction Therapy
A. Blázovics

Oxidative stress is a key modulator, which modifies the ligand-receptor interactions extracellularly and intracellularly, and influences gene expression. Free radicals can act as secondary messengers in several transduction pathways, and take part in the activation of chemotactic cytokines and surface adhesion molecules etc.

Oxidative stress can induce stress response genes, and moderate oxidative stress by down regulating the gene expression of several genes. DNA synthesis, selective gene expression, enzyme activation and modification of cell proliferation are involved in redoxy signal mechanisms.

Moderate free radical production can modify the function of kinases or directly activate the transcription factors, thereby also influencing the gene regulation in the nucleus.

The “antioxidant” concept has meaning only in defense against free radicals for a long period. Its importance is not doubtful in the therapy of diseases in which free radicals are also involved. “Janus face” antioxidants can stop protein phophorilation and the inhibition of activation of transcription factors. They can also therefore stop cell proliferation and injure the adaptation mechanisms against oxidative stress. The direct roles of these antioxidants in original forms are doubtful in transduction therapy.


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Signal Transduction by the Cytoplasmic Domain of Neuregulin-1 and its Roles During Neuronal Aging
J. Bao

Transmembrane isoforms of Neuregulin-1 (NRG1) contain an extracellular domain, a transmembrane domain, and a highly conserved intracellular domain. Several recent findings suggest a role of NRG1 signaling in synaptic maintenance and possibly neurodegenerative diseases. The extracellular domain of NRG1 binds to the ErbB family of receptor tyrosine kinases to activate signaling cascades in target cells. This “forward signaling” pathway regulates the expression of receptors for several neurotransmitters. We have recently found that the intracellular domain of NRG1 (NRG1-ICD) translocates into the nucleus where it regulates gene expression. Specifically, this “backward signaling” pathway, which is enhanced by synaptic activity, up-regulates postsynaptic density protein 95 (PSD-95) expression. PSD-95 is a scaffolding protein enriched in post-synaptic structures. NRG1-ICD enhances the transcriptional activity of the PSD-95 promoter by binding to a zinc-finger transcription factor, Eos. Up-regulation of PSD-95 could contribute to normal physiological processes, such as synaptic plasticity for learning and memory, it may also be associated with neuronal excitotoxicity under pathological conditions. NRG1-ICD is specifically associated with neuritic plaques in the brain of patients with Alzheimer's disease. Loss of synaptic connections is found in the brain of Alzheimer’s disease. Therefore, further studies of the signal transduction pathways activated by NRG1-ICD will provide insight into the molecular mechanisms underlying learning and memory, as well as a basis for possible clinical interventions for age-related neurodegeneration diseases.


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The Phosphoinositide 3-Kinase (PI3K)/AKT Signaling Pathway as a Therapeutic Target for the Treatment of Human Acute Myeloid Leukemia (AML)
A.M. Martelli, G. Tabellini, R. Bortul, M. Nyåkern, P.L. Tazzari, C. Evangelisti and L. Cocco

The PI3K/Akt signaling network regulates cell growth and apoptosis, and its constitutive activation has been implicated in the pathogenesis of a variety of malignancies. Recent studies suggest that PI3K/Akt signaling is frequently up-regulated in blast cells from AML patients and strongly contributes to proliferation, survival, and drug-resistance of these cells. Up-regulation of this network in AML may due to several reasons, including FLT3 and Ras activating mutations, increased levels of PI3K p110δ catalytic subunit, lack of PTEN lipid phosphatase expression, and autocrine production of growth factors. Small molecules designed to specifically target key components of this signal transduction network have been shown to induce apoptosis and/or increase conventional drug sensitivity of AML blasts in vitro. Therefore, these inhibitory molecules are being developed for clinical use either as single therapeutic agents or in combination with other forms of therapy. Nevertheless, PI3K/Akt blockade in vivo might have detrimental systemic side effects, given the multiple physiological roles played by this pathway, such as insulin-dependent glucose transport. Herein, we summarize our knowledge about PI3K/Akt signaling in AML and we highlight several pharmacological inhibitors which could be used in the future for treating this too often fatal hematological disorder.