Current Signal Transduction Therapy

ISSN: 1574-3624

Current Signal Transduction Therapy
Volume 2, Number 2, May 2007

Contents


Targeting Neurotrophic Signal Transduction Pathways in the Treatment of Mood Disorders Pp. 101-110
T.D. Gould and H.K. Manji
[Abstract]


Smad-Signaling in Mammary Gland Development and Tumorigenesis Pp. 111-120
V. Gupta, A. Thiagalingam and S. Maheswaran
[Abstract]


Nitric Oxide: Friendly Rivalry in Tuberculosis Pp. 121-128
S. Mukhopadhyay, S. Nair and S.E. Hasnain
[Abstract]


Potential Utilization of Bystander / Abscopal-Mediated Signal Transduction Events in the Treatment of Solid Tumors Pp. 129-143
M.E. Peters, M.M. Shareef, S. Gupta, M. Zagurovskaya-Sultanov, M. Kadhim, M. Mohiuddin and M.M. Ahmed
[Abstract]


Mathematical Modeling of the Cancer Cell’s Control Circuitry: Paving the Way to Individualized Therapeutic Strategies Pp. 145-155
R.P. Araujo, E.F. Petricoin and L.A. Liotta
[Abstract]


Oncogene-Directed Therapies as Modulators of Cancer Coagulopathy, Angiogenesis and Tumor-Vascular Interface Pp. 157-163
J. Rak, C. Milsom, L. May and J. Yu
[Abstract]


Molecular Rationales for Signal Transduction Therapy and Chemoprevention of BRCA1-Related Breast and Ovarian Tumours Pp. 165-173
P. Tagliaferri, P. Tassone, A. Pietragalla, M.S. Rotundo, V. Barbieri, A. Budillon, M. Caraglia, F.S. Costanzo and S. Venuta
[Abstract]


Blocking Apoptotic Intracellular Signaling Cascades with Cell Permeable Peptides Pp. 175-179
A. Zine, J. Beckmann and C. Bonny, A. Uziel
[Abstract]




Abstracts


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Targeting Neurotrophic Signal Transduction Pathways in the Treatment of Mood Disorders
T.D. Gould and H.K. Manji

Mood disorders such as bipolar disorder and unipolar depression are pervasive diseases associated with high rates of morbidity and mortality. There exists an urgent need for novel medications. Current compounds often do not bring about full remission, and if they do, it is only after a minimum of many weeks, if not months of treatment. Alterations in signaling pathways represent a likely source of pathogenesis. Dynamic regulation of complex signaling pathways plays a critical role in higher order brain functions, which include the regulation of mood, cognition, and sense of self and reality; thus implicating their involvement in mood disorder pathophysiology and pathogenesis. Impairments in neuroplasticity in the brains of patients suffering from mood disorders suggest that novel medications designed to attenuate impairments in these processes may have efficacy in their treatment. Further, since the onset of the vast majority of psychotrophic medications takes an extended period of treatment, it is a widely held belief that these drugs may act by modulation of critical neuronal signaling pathways and the resultant changes in gene expression and protein function. Preclinical, and some clinical, evidence implicates the action of specific neurotrophic signaling pathways in the downstream mechanism of action of medications useful for the treatment of mood disorders. We discuss specific signaling pathway and molecular treatment targets that are being considered for the development of novel treatments for mood disorders.


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Smad-Signaling in Mammary Gland Development and Tumorigenesis
V. Gupta, A. Thiagalingam and S. Maheswaran

The Transforming Growth Factor-β (TGFβ) superfamily of cytokines regulates a myriad of cellular processes including proliferation, differentiation and tumorigenesis. Signaling by these growth regulatory molecules is propagated by ligand-induced hetero-oligomerization of distinct type II and type I serine/threonine kinase receptors, which result in activation of receptor-activated Smad proteins as well as Smad-independent pathways. Disruption of TGFβ induced signaling can contribute to development and progression of human breast cancer. The role of Smad-signaling in mammary gland development and tumorigenesis will be the focus of this review.


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Nitric Oxide: Friendly Rivalry in Tuberculosis
S. Mukhopadhyay, S. Nair and S.E. Hasnain

Immune dependent growth and development of infectious agents and pathogenesis are increasingly being recognized as crucial for designing efficient immunotherapeutic approaches for Mycobacterium tuberculosis. Nitric oxide (NO) in the context of mycobacterial infection is an essential component of the protective armory of host innate immune system. However, the ability of NO to suppress host immune response questions the traditional view that production of NO is actually designed for anti-microbial mechanism. Human tuberculosis is considered as a prime example of a disease controlled dominantly by cell-mediated and not by humoral immunity. Interleukins like IL-12 and IL-8 play important roles in anti-tuberculosis immunity. While IL-8 has a central role in leukocyte recruitment to areas of granuloma formation, IL-12 helps in the generation of effective cell-mediated immune response in tuberculosis. NO shows an ability to inhibit mycobacterial infection by inducing innate-cytotoxic response and by increasing IL-8 induction. However, it may become a problem in later phase when it converts a protective Th1 response to a subversive Th2 response mainly by inhibiting IL-12 cytokine, thus acting as a potential regulator of Th1/Th2 response. This review intends to explore the possibilities that can be envisioned for exploring NO from immunotherapeutic perspectives in mycobacterial immunity.


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Potential Utilization of Bystander / Abscopal-Mediated Signal Transduction Events in the Treatment of Solid Tumors
M.E. Peters, M.M. Shareef, S. Gupta, M. Zagurovskaya-Sultanov, M. Kadhim, M. Mohiuddin and M.M. Ahmed

A transformed cell among a group of normal cells exerts a dynamic influence for clonal growth and mass transformation. Likewise, a treatment-induced damaged cell might exert deleterious signal to either neighboring or distal cells. These signals that elicit either transformation or cell death are classified under two independent phenomena. These two phenomena are called (1) Abscopal effect and (2) Bystander effect. There are several agents that have been reported to induce abscopal and bystander effects. Ionizing radiation and ultraviolet radiation are prime inducers of abscopal and bystander effects. In addition, localized therapies for tumor control such as gene therapy approaches, prodrug conversion based chemotherapy approaches, and surgical procedures are significant inducers of either abscopal or bystander effects. The proposed mechanisms that have been reported in literature clearly indicate pivotal roles of cytokine and ceramide signaling leading to the activation of pro-survival proteins and/or pro-apoptotic proteins. Together these pathways provide distinct differences between abscopal and bystander effects that are of particular interest in modern cancer therapeutics. The most exciting future direction of bystander/ abscopal biology in terms of cancer therapeutics will potentially arise from the use of stem cells. In this review, a critical evaluation of potential benefits of abscopal / bystander effects mediated signaling pathways in relation to cancer therapeutics are discussed in detail.


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Mathematical Modeling of the Cancer Cell’s Control Circuitry: Paving the Way to Individualized Therapeutic Strategies
R.P. Araujo, E.F. Petricoin and L.A. Liotta

Cancer is a disease of signal transduction in which the dysregulation of the network of intracellular and extracellular signaling cascades is sufficient to thwart the cell’s finely-tuned biochemical control mechanisms. A keen interest in the mathematical modeling of cell signaling networks and the regulation of signal transduction has emerged in recent years, and has produced a glimmer of insight into the sophisticated feedback control and network regulation operating within cells. In this review, we present an overview of published theoretical studies on the control aspects of signal transduction, emphasizing the role and importance of mechanisms such as ‘ultrasensitivity’ and feedback loops. We emphasize that these exquisite and often subtle control strategies represent the key to orchestrating ‘simple’ signaling behaviors within the complex intracellular network, while regulating the trade-off between sensitivity and robustness to internal and external perturbations. Through a consideration of these apparent paradoxes, we explore how the basic homeostasis of the intracellular signaling network, in the face of carcinogenesis, can lead to neoplastic progression rather than cell death. A simple mathematical model is presented, furnishing a vivid illustration of how ‘control-oriented’ models of the deranged signaling networks in cancer cells may enucleate improved treatment strategies, including patient-tailored combination therapies, with the potential for reduced toxicity and more robust and potent antitumor activity.


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Oncogene-Directed Therapies as Modulators of Cancer Coagulopathy, Angiogenesis and Tumor-Vascular Interface
J. Rak, C. Milsom, L. May and J. Yu

Oncogenic lesions in the cancer cell genome not only alter the intrinsic properties of cancer cells themselves, but also trigger signaling events, the effects of which impact the relationship between tumors and their surrounding host tissues, including the vascular system. Manifestations of the latter include the onset and progression of tumor angiogenesis, and systemic activation of the hemostatic system, a process also known as cancer coagulopathy, or Trousseau syndrome. Indeed, tumor growth, invasion and metastasis are profoundly affected by the properties of the tumor - vascular interface. We postulated earlier that the link between the expression of cancer-causing signaling alterations and cancer coagulopathy is at least twofold. First, cancer coagulopathy may emerge indirectly, as an unspecific consequence of vascular permeability and other features of tumor-associated vascular growth, including the pro- and anticoagulant actions of certain angiogenic mediators, some of which (e.g. VEGF) are direct regulatory targets of oncogenes and tumor suppressors. Second, activated oncogenes (K-ras, EGFR or PML-RARα, MET), and/or inactivation of tumor suppressors (e.g. p53 or PTEN) may de-regulate some of the hemostatic proteins more directly, i.e. through changes in expression of tissue factor (TF), plasminogen activation inhibitor 1 (PAI-1) and cyclooxygenase 2 (COX-2) [1-4]. In addition to TF expression and release as plasma microvesieles, mutant K-ras may also upregulate expression of thrombin receptors (PAR-1) by cancer cells, thereby possibly rendering such cells hypersensitive to signals emanating from the hemostatic system (e.g. pericellular thrombin). Here, we present an argument that anti-cancer signal transduction inhibitors, also known as 'targeted agents' (e.g. Gleevec, Iressa, Erbitux, ATRA) could modulate various vascular processes in cancer, including angiogenesis and cancer coagulopathy, i.e. act as cancer - specific indirect antiangiogenic agents, possibly with a distinct element of anticoagulant activity.


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Molecular Rationales for Signal Transduction Therapy and Chemoprevention of BRCA1-Related Breast and Ovarian Tumours
P. Tagliaferri, P. Tassone, A. Pietragalla, M.S. Rotundo, V. Barbieri, A. Budillon, M. Caraglia, F.S. Costanzo and S. Venuta

The design of novel therapeutic strategies based on tumour molecular features and specific carcinogenetic pathways is a compelling issue. Tumours arising in BRCA1-defective individual carriers constitute a specific entity which resembles the basal-like molecular phenotype for breast tumours, while BRCA1-defective ovarian cancer has a molecular signature which is also shared by a substantial amount of sporadic tumours. Several important issues are derived from the role of BRCA1 gene product in critical cell functions like DNA repair, transcription regulation and cell cycle checkpoint control. It has been recently demonstrated that the loss of such functions in BRCA1-defective tumours results in a specific profile of sensitivity to anti-cancer drugs. Moreover, BRCA1 appears to retain a critical role in the response of cells to stress as well as to the growth promoting stimuli generated by estrogens and peptide growth factors. Therefore, it is conceivable that loss of a functional BRCA1 produces a general de-arrangement of cellular signaling which might allow the identification of specific and high priority targets and lead to individualized signal transduction-based anti-tumour approaches. We will review the most important findings related to BRCA1 effects on cellular signaling in order to depict a general scenario for selective chemopreventive and therapeutic strategies.


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Blocking Apoptotic Intracellular Signaling Cascades with Cell Permeable Peptides
A. Zine, J. Beckmann and C. Bonny, A. Uziel

Cells are continuously adapting to changes in their environment by activating extracellular stimuli-dependent signal transduction cascades. These cascades, or signaling pathways, culminate both in changes in genes expression and in the functional regulation of pre-existing proteins. The Mitogen-Activated Protein Kinases (MAPKs) constitute a structurally related class of signaling proteins whose distinctive feature is their ability to directly phosphorylate, and thereby modulate, the activity of the transcription factors that are targets of the initial stimuli. The specificity of activation of MAPK signaling modules is determined, at least for an important part, by the specificity of the protein-protein contacts that are required for the propagation of the signal. We will discuss how it is possible to interfere with MAPK signaling by using short cell-permeable peptides able to block, through a competitive mechanisms, relevant protein-protein contacts, and their effects on signaling and cell function.