Current Molecular Medicine - Volume 9, Issue 5, 2009

Virus-induced respiratory disease accounts for the majority of hospitalizations of young children during the winter months. The major viral causes of lower respiratory tract disease in infants and children are respiratory syncytial virus (RSV), rhinovirus, metapneumovirus (hMPV), parainfluenza virus 3 (PIV-3), and influenza. The primary antiviral mechanism involves the activation of cytotoxic T cells and the clearance of virus-infected epithelial cells, and Toll-like receptors that recognize microbial molecular patterns are thought to initiate and orchestrate the immune response. Here, we review the role of Toll-like receptors in modulating the immune response to respiratory viral disease, including the role of maturation of the TLR system in early life.

Apoptosis, a programmed cell death mechanism, is a fundamental process during the normal development and somatic maintenance of all multicellular organisms and thus is highly conserved and tightly regulated through numerous signaling pathways. Apoptosis is of particular clinical importance as its dysregulation contributes significantly to numerous human diseases, primarily through changes in the expression and activation of key apoptotic regulators. Each of the four families of heterotrimeric G proteins (Gs, Gi/o, Gq/11 and G12/13) has been implicated in numerous cellular signaling processes, including proliferation, transformation, migration, differentiation, and apoptosis. Heterotrimeric G protein signaling is an important but not widely studied mechanism regulating apoptosis. G protein Signaling and Apoptosis broadly cover two large bodies of literature and share numerous signaling pathways. Examination of the intersection between these two areas is the focus of this review. Several studies have implicated signaling through each of the four heterotrimeric G protein families to regulate apoptosis within numerous disease contexts, but the mechanism(s) are not well defined. Each G protein family has been shown to stimulate and/or inhibit apoptosis in a context-dependent fashion through regulating numerous downstream effectors including the Bcl-2 family, NF-κB, PI3 Kinase, MAP Kinases, and small GTPases. These cell-type specific and G protein coupled receptor dependent effects have led to a complex body of literature of G protein regulation of apoptosis. Here, we review the literature and summarize apoptotic signaling through each of the four heterotrimeric G protein families (and the relevant G protein coupled receptors), and discuss limitations and future directions for research on regulating apoptosis through G protein coupled mechanisms. Continued investigation in this field is essential for the identification of important targets for pharmacological intervention in numerous diseases.

Hearing loss is the most common sensory disorder, present in 1 of every 500 newborns. To date, 46 genes have been identified that cause nonsyndromic hearing loss, making it an extremely heterogeneous trait. This review provides a comprehensive overview of the inner ear function and expression pattern of these genes. In general, they are involved in hair bundle morphogenesis, form constituents of the extracellular matrix, play a role in cochlear ion homeostasis or serve as transcription factors. During the past few years, our knowledge of genes involved in hair bundle morphogenesis has increased substantially. We give an up-to-date overview of both the nonsyndromic and Usher syndrome genes involved in this process, highlighting proteins that interact to form macromolecular complexes. For every gene, we also summarize its expression pattern and impact on hearing at the functional level. Gene-specific cochlear expression is summarized in a unique table by structure/cell type and is illustrated on a cochlear cross-section, which is available online via the Hereditary Hearing Loss Homepage. This review should provide auditory scientists the most relevant information for all identified nonsyndromic deafness genes.

Recently, lipoxins (LXs) and resolvins (Rvs) have become the topic of intense interest because of expanding views of their action, particularly in chronic disorders where unresolved inflammation is a key factor leading to colon carcinogenesis. Rvs are biosynthesized from omega-3 fatty acids eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) via cyclooxygenase-2/lipoxygenase (COX-2/LOX) pathways; Rvs are shown to dramatically reduce dermal inflammation, peritonitis, dendritic cell migration, and interleukin production. This explains that dietary supplementation of omega-3 fatty acids generates potent local endogenous mediators that control inflammation. LXs are biosynthesized from COX-2/LOX pathways. Metabolites of 15-LOX-1 and 2 are anti-tumorigenic; similarly, 15-epi-LXA4 synthesized during COX-2 acetylation by low doses of aspirin too possesses anti-tumorigenic effects. Acetylating nonsteroidal anti-inflammatory drugs (NSAIDs), like aspirin, switches COX-2 from forming PGE2 (promoting tumorigenesis) to 15-epi-LXA4 (antitumorigenesis). LXs and Rvs are endogenously generated during the spontaneous resolution phase. These newly identified LXs and Rvs have proved to be potent regulators of both leukocytes and cytokine productions, thereby regulating the events of interest in inflammation and resolution. In light of existing knowledge on interconnected pathways of pro-inflammatory mediators (leukotrienes, chemokines (IL8, SDF-1α, MIP-1α, MCP-1,2 etc), and cytokines (IL3, IL6, IL12, IL-1β, GM-CSF, B94, TNF-α etc)), the anti-inflammatory properties of pro-resolving mediators in preventing chronic inflammation which leads to carcinogenesis needs further understanding. In this review, we explore the mechanisms that trigger formation of LXs and Rvs, to highlight the relative importance of LXs and Rvs in carcinogenesis in relation to pro-inflammatory mediators.

Malignant gliomas are the most common primary brain tumors. Despite efforts to find effective treatments, these tumors remain incurable. The failure of malignant gliomas to respond to conventional cancer therapies may reflect the unique biology of these tumors, underscoring the need for new approaches in their investigation. Recently, progress has been made in characterization of the molecular pathogenesis of glioblastoma using a developmental neurobiological perspective, by exploring the role of signaling pathways that control the differentiation of neural stem cells along the glial lineage. The transcription factor STAT3, which has an established function in neural stem cell and astrocyte development, has been found to play dual tumor suppressive and oncogenic roles in glial malignancy depending on the mutational profile of the tumor. These findings establish a novel developmental paradigm in the study of glioblastoma pathogenesis and provide the rationale for patient-tailored therapy in the treatment of this devastating disease.

Although the aetiology of MS remains elusive, several genetic approaches have provided clues to the underlying molecular pathogensis. In addition to the well known association to HLA class II alleles, weak but highly significant association to the interleukin-7 receptor and interleukin-2 receptor genes has recently been established. A series of other promising candidate genes identified in large genome screens are under evaluation. The genetic predisposition to MS is so far shown to be mediated by common polymorphisms in genes encoding molecules involved in T cell activation and homeostasis, but only a small proportion of the potential susceptibility genes have yet been identified. Analyses of transcribed immune receptor genes have revealed evidence of antigen-driven clonal expansion of lymphocytes, and may also provide tools for charting their specificites. Recently, attempts to identify disease-associated genes through transcriptional profiling have revealed new candidate players in MS pathogenesis. Whereas genetic studies in humans may identifiy individual molecular players, transgenic animal models allow detailed examination of molecular pathways. These studies have shown that in addition to altered protein function, alteration of gene expression may contribute to disease development. We here review how different genetic approaches can be combined to elucidate the immunopathogenesis of MS.

Deregulation of the PI3K pathway is common in human cancer. The basic players in this pathway are the kinases PI3K and AKT and the phosphatase PTEN. This review will summarize some of the key animal models that have helped us understand this signaling network and its contribution to tumorigenesis. Recently, great advances in cancer mouse models have been achieved [1]. While germline deletion often affects the development of the organism and can result in embryonic lethality, conditional knockout mouse models offer the possibility of inducing gene deletion in the adult organism. Another useful strategy involves the inactivation of enzyme function by introducing small mutations in the gene sequence, thereby maintaining the protein in an inactivated state and mimicking protein inhibition with drugs. Combining tissue-specific expression of PI3K and AKT with a secondary oncogenic event, for example, leads to the development of specific tumors. Such models are more accurate for growth studies of human tumors than those involving xenograft tumors, due to the interconnection of the tumors with blood vessels. These studies will improve the pharmacological analysis of drug candidates. With the discovery of oncogenic mutations in members of the PI3K pathway, mouse lines harboring these mutations are being developed in order to imitate the molecular features of a human tumor. Using these models for drug testing may enable more accurate prediction of the effects that a specific drug will have on a patient.

Metastasis is a major cause of morbidity and mortality in patients with cancer. The molecular mechanisms that control metastasis are related to alterations in various oncogenes, tumor suppressor genes, metastasis suppressor genes, and growth factors and their receptors. These abnormalities affect the downstream signal transduction pathways involved in the control of cell growth and other malignant properties. One of the most recognized signal transduction pathways involves the signal transducer and activator of transcription 3 (STAT3) protein. STAT3, known to be activated by numerous cytokines, growth factors, and oncogenic proteins, is constitutively phosphorylated in several clinical cancer specimens and cell lines, leading to cell transformation and tumorigenesis. STAT3 target genes are involved in multiple steps of metastasis, including invasion, cell survival, self-renewal, angiogenesis, and tumor-cell immune evasion. Furthermore, the inhibition of STAT3 by a variety of mechanisms can exert anti-tumor and anti-metastasis effects. These findings suggest that STAT3 might be an excellent target for therapeutic intervention in tumor metastases. This review highlights the pivotal role of STAT3 in tumor metastases and in therapeutic strategies to target the STAT3 signaling pathway for the inhibition of metastases.

Neurofibromatosis type 1 (NF1) is a developmental and cancer predisposing syndrome resulting from haploinsufficiency or alteration in neurofibromin, a multifunctional protein that acts in various signaling pathways affecting morphogenetic processes and cell proliferation. Neurofibromin deficiency deregulates Ras/Raf/MEK/ERK and Ras/PI3K/AKT/PKB/mTOR signaling networks and intersected pathways including the cAMP-dependent protein kinase A (PKA) and the Rho-cofillin which acts on actin cytoskeleton reorganization, cell motility and adhesion. As the neurofibromin-mediated pathways are associated with biological effects depending on the cell lineage, deregulation induced by NF1 mutation clearly has cell type-specific effects. This review summarizes our increasing knowledge of NF1 as a disease rooted in defective developmental mechanisms that can also influence the potential for malignant growth. The cardinal features of NF1 patients, at birth and during life involve the cardiovascular, connective/skeletal and central nervous systems, as they reflect the NF1 mutation sensitivity of cell lineages committed to specifying these systems during embryonic development. A switch to neoplastic transformation may also occur in both the prenatal and postnatal life in cancer initiating cells of defined lineages, with the cooperation of a genetically and epigenetically modified tumor microenvironment. We emphasize how much of our current knowledge of the pathomechanisms of NF1 clinical signs and cancer has come from engineered mouse models and in vitro primary cells and cell lines exposed to inhibitors of signaling molecules. Advances in our knowledge of the developmental defects primed by the loss neurofibromin should reveal further associations between given NF1 mutations and tissue-specific symptoms, thus improving the clinical management of the patients.

Heat shock protein 90 (HSP90) family of proteins are ubiquitous molecular chaperones that are involved in folding, activation, maturation and assembly of many proteins that include essential mediators of signal transduction and cell cycle progression. They are abundant in eukaryotic cells and localized to the cytoplasm, mitochondria as well as the endoplasmic reticulum under normal conditions, making up 1-2% of all cellular proteins. HSP90 proteins have increased expression in a number of malignancies. A large number of HSP90 client proteins have been shown to be necessary for the development, proliferation and survival of specific types of cancers. HSP90 inhibition can affect multiple oncogenic pathways and involved proteins, therefore make it an attractive target for drug development. This article serves as an overview of the pre-clinical data and clinical trial data on HSP90 inhibitor 17-AAG in different malignancies. 17-AAG has shown significant antitumor activity against a spectrum of cancers in the pre-clinical studies and information from various phases of clinical trials is growing. The potential indication of 17-AGG for the treatment of refractory multiple myeloma now awaits for the results of two phase III studies. More work needs to be done before the broader oncological use of HSP90 inhibitors in the area of defining HSP90 client proteins, understanding the mechanism of HSP90 actions, identifying reliable surrogate markers for HSP90 inhibition in vivo and optimizing drug delivery and efficacy.