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PubMed2005

Molecular genetics of meningiomas.

In this article the authors provide a brief description of the current understanding of meningioma genetics. Chromosome 22 abnormalities, especially in the Neurofibromatosis Type 2 (NF2) gene, have been associated with meningioma development. Loss of heterozygosity of chromosome 22 occurs in approximately 60% of meningiomas; however, loss of NF2 gene function occurs in only one third of these lesions. This discrepancy supports the theory that a second tumor suppressor gene exists on chromosome 22, and the authors introduce several possible gene candidates, including BAM22, LARGE, INI1, and MN1 genes. Deletions of 1p have also been shown to correlate with meningioma progression. The genetic similarities and differences among sporadic, NF2-associated, pediatric, and radiation-induced meningiomas are discussed, with the observation that the nonsporadic meningiomas have a higher incidence of multiple chromosomal abnormalities at presentation. Ultimately, a better understanding of the molecular pathways of meningioma tumorigenesis will lead to new, successful treatments.

Animals↗
PubMed2006

Evidence that TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK pathway mediates constitutive NF-kappaB activation and proliferation in human head and neck squamous cell carcinoma.

Constitutively activated nuclear factor-kappaB (NF-kappaB) has been associated with a variety of aggressive tumor types, including head and neck squamous cell carcinoma (HNSCC); however, the mechanism of its activation is not fully understood. Therefore, we investigated the molecular pathway that mediates constitutive activation of NF-kappaB in a series of HNSCC cell lines. We confirmed that NF-kappaB was constitutively active in all HNSCC cell lines (FaDu, LICR-LON-HN5 and SCC4) examined as indicated by DNA binding, immunocytochemical localization of p65, by NF-kappaB-dependent reporter gene expression and its inhibition by dominant-negative (DN)-inhibitory subunit of NF-kappaB (IkappaBalpha), the natural inhibitor of NF-kappaB. Constitutive NF-kappaB activation in HNSCC was found to be due to constitutive activation of IkappaBalpha kinase (IKK); and this correlated with constitutive expression of phosphorylated forms of IkappaBalpha and p65 proteins. All HNSCC showed the expression of p50, p52, p100 and receptor-interacting protein; all linked with NF-kappaB activation. The expression of constitutively active NF-kappaB in HNSCC is mediated through the tumor necrosis factor (TNF) signaling pathway, as NF-kappaB reporter activity was inhibited by DN-TNF receptor-associated death domain (TRADD), DN-TNF receptor-associated factor (TRAF)2, DN-receptor-interacting protein (RIP), DN-transforming growth factor-beta-activated kinase 1 (TAK1), DN-kappa-Ras, DN-AKT and DN-IKK but not by DN-TRAF5 or DN-TRAF6. Constitutive NF-kappaB activation was also associated with the autocrine expression of TNF, TNF receptors and receptor-activator of NF-kappaB and its ligand in HNSCC cells but not interleukin (IL)-1beta. All HNSCC cell lines expressed IL-6, a NF-kappaB-regulated gene product. Furthermore, treatment of HNSCC cells with anti-TNF antibody downregulated constitutively active NF-kappaB, and this was associated with inhibition of IL-6 expression and cell proliferation. Our results clearly demonstrate that constitutive activation of NF-kappaB is mediated through the TRADD-TRAF2-RIP-TAK1-IKK pathway, making TNF a novel target in the treatment of head and neck cancer.

Carcinoma, Squamous Cell↗
PubMed2006

Inhibition of zebrafish fin regeneration using in vivo electroporation of morpholinos against fgfr1 and msxb.

Increased interest in using zebrafish as a model organism has led to a resurgence of fin regeneration studies. This has allowed for the identification of a large number of gene families, including signaling molecules and transcription factors, which are expressed during regeneration. However, in cases where no specific inhibitor is available for the gene product of interest, determination of a functional role for these genes has been difficult. Here we demonstrate that in vivo electroporation of morpholino oligonucleotides is a feasible approach for protein knock-down during fin regeneration. Morpholino oligonucleotides against fgfr1 and msxb were utilized and knock-down of both proteins resulted in reduced fin outgrowth. Importantly, Fgfr1 knock-down phenocopied outgrowth inhibition obtained with an Fgfr1 inhibitor. Furthermore, this method provided direct evidence for a functional role for msxb in caudal fin regeneration. Finally, knock-down of Fgfr1, but not Msxb, affected the blastemal expression of msxc, suggesting this technique can be used to determine epistasis in genetic pathways affecting regeneration. Thus, this convenient reverse genetic approach allows researchers to quickly (1) assess the function of genes known to be expressed during fin regeneration, (2) screen genes for functional relevance during fin regeneration, and (3) assign genes to the molecular pathways underlying fin regeneration.

Animals↗
PubMed2006

K-ras, p53 mutations, and microsatellite instability (MSI) in gallbladder cancer.

Despite the considerable progress in understanding the molecular pathology of carcinogenesis, the genetic mechanisms underlying the development and progression of gallbladder cancer (GC) are poorly understood. The survival of GC patients is generally poor. Therefore, it is very useful to define valuable prognostic factors. The most extensively studied oncogenes in gallbladder carcinogenesis are ras, commonly mutated in neoplasms of the gastrointestinal tract. K-ras oncogene is altered in a subset of gallbladder patients and mainly in those having anomalous junction of the pancreaticobiliary tract. Most of the studies of genetic abnormalities in GC have focused on p53 gene. p53 mutation/overexpression and/or LOH is present in more than 50% of gallbladder carcinomas, suggesting an important role in their pathogenesis. However, these results have not any predictive value yet. Moreover, the involvement of an alternative molecular pathway, that of microsatellite instability (MSI), is found in a limited group of GC patients. Additional research is necessary to establish its possible relation to defects of the mismatch repair (MMR) system and its proposed prognostic significance. Further elucidation of the molecular events specific to GC will help to identify novel molecular targets for the diagnosis and clinical management of the patients.

Chromosomal Instability↗
PubMed2005

Regulating the dynamics of EGF receptor signaling in space and time.

The epidermal growth factor receptor (EGFR) signaling cascade represents one of the cardinal pathways that transmits information between cells during development in a broad range of multicellular organisms. Most of the elements that constitute the core EGFR signaling module, as well as a variety of negative and positive modulators, have been identified. Although this molecular pathway is utilized multiple times during development, the spatial and temporal features of its signaling can be modified to fit a particular developmental setting. Recent work has unraveled the various mechanisms by which the EGFR pathway can be modulated.

Animals↗
PubMed2000

Leg development in flies versus grasshoppers: differences in dpp expression do not lead to differences in the expression of downstream components of the leg patterning pathway.

All insect legs are structurally similar, characterized by five primary segments. However, this final form is achieved in different ways. Primitively, the legs developed as direct outgrowths of the body wall, a condition retained in most insect species. In some groups, including the lineage containing the genus Drosophila, legs develop indirectly from imaginal discs. Our understanding of the molecular mechanisms regulating leg development is based largely on analysis of this derived mode of leg development in the species D. melanogaster. The current model for Drosophila leg development is divided into two phases, embryonic allocation and imaginal disc patterning, which are distinguished by interactions among the genes wingless (wg), decapentaplegic (dpp) and distalless (dll). In the allocation phase, dll is activated by wg but repressed by dpp. During imaginal disc patterning, dpp and wg cooperatively activate dll and also indirectly inhibit the nuclear localization of Extradenticle (Exd), which divide the leg into distal and proximal domains. In the grasshopper Schistocerca americana, the early expression pattern of dpp differs radically from the Drosophila pattern, suggesting that the genetic interactions that allocate the leg differ between the two species. Despite early differences in dpp expression, wg, Dll and Exd are expressed in similar patterns throughout the development of grasshopper and fly legs, suggesting that some aspects of proximodistal (P/D) patterning are evolutionarily conserved. We also detect differences in later dpp expression, which suggests that dpp likely plays a role in limb segmentation in Schistocerca, but not in Drosophila. The divergence in dpp expression is surprising given that all other comparative data on gene expression during insect leg development indicate that the molecular pathways regulating this process are conserved. However, it is consistent with the early divergence in developmental mode between fly and grasshopper limbs.

Animals↗
PubMed2002

Intramuscular force transmission.

The architectural form of skeletal muscle, the pattern of activity/usage between neighbouring fibres, and the pathways for lateral and lengthwise tension delivery are all of interest in understanding muscle function and dysfunction. We have attempted to contribute to understanding of intramuscular force transmission by investigating the functional relationships between coactive motor units, and by examining the detailed molecular and morphological features at sites of tension transfer. We found that tension delivery is modulated by interaction between active and inactive fibres, that many muscle fibre terminations feature structural coupling between fibres, and that sites of tension delivery feature a variety of proteins including acetylcholinesterase, NCAM, dystrophin and two splice variants of the alpha7 integrins. We conclude that structural and molecular pathways exist to deliver force within, along, and between muscle fibres, and that the quality/quantity of tension delivered from any single fibre is at least partly a consequence of whether its neighbouring fibres are synchronously coactive.

Animals↗
PubMed2006

Characterization of differential gene expression profiles in diabetic embryopathy using DNA microarray analysis.

OBJECTIVE: The molecular mechanisms by which maternal diabetes impairs embryogenesis are not established. This study aimed to determine the developmental genes and molecular pathways that are involved in diabetic embryopathy, by comparing gene expression profiles in the yolk sacs between the embryos of diabetic and control rats by using DNA microarray analysis. STUDY DESIGN: Diabetes was induced in female rats by injecting streptozotocin (65 mg/kg) intravenously. Glucose levels were controlled by subcutaneously implanting insulin pellets. The female rats were mated with normal male rats. At gestation day 4, the insulin pellets were removed from a group of animals, making them hyperglycemic. The animals with insulin pellets served as controls. At gestational day 12, embryos were explanted, and yolk sacs were collected. Total RNA, free of DNA contamination, was extracted from the yolk sacs. Complementary DNA probes were synthesized, labeled with Cy3 and Cy5 fluorescent dyes, and used to hybridize rat oligo-array containing 10,000 genes. Data were analyzed by using 1-sample t test on log2 ratios, with P < .05 representing a significant difference. The changes in expression levels of important genes were verified with the use of a real-time polymerase chain reaction (PCR). RESULTS: Five microarray experiments produced consistent results. A total of 101 genes were found to be differentially expressed between the embryos of diabetic and control rats. Analyses that used PathwayAssist (Ariadne Genomics, Rockville, MD) revealed a number of potential signaling pathways and genes involved in insulin signaling and stress response (insulin 2, insulin-binding protein 1, GST pi1), cell growth (GAP43, CSF1R, HGF), calcium signaling (calbindin 3, CBP A6), and PKC signaling (PKCBP beta15, FABP5), in concert with prior biochemical and molecular findings. CONCLUSION: These observations show significant alterations in expression of developmental and stress response genes in diabetic embryopathy, and demonstrate, for the first time, that the yolk sac cells express insulin during early development. In addition, these data also demonstrate that hyperglycemia induces altered gene expression, resulting in aberrant cell signaling, morphogenesis, and embryopathy.

Animals↗
PubMed2002

Roles of the Werner syndrome protein in pathways required for maintenance of genome stability.

Werners syndrome is a disease of premature aging where the patients appear much older than their chronological age. The gene codes for a protein that is a helicase and an exonuclease, and recently we have learned about some of its protein interactions. These interactions are being discussed as they shed light on the molecular pathways in which Werner protein participates. Insight into these pathways brings insight into the aging process.

Catalysis↗
PubMed2003

Osteopontin and colon cancer progression.

Human colon cancer affects nearly 150,000 patients and results in 60,000 deaths in the United States per year. Despite significant advances in the management of the colon cancer patient, little change in survival rates has been appreciated over the past 50 years. The primary cause of death relates to the development of distant metastases to organs such as the liver and lungs. Colon cancer represents an important disease to study in order to better understand tumor progression and metastasis primarily because there is almost a stepwise advancement of the disease that is marked by measurable genetic and associated phenotypic alterations. Metastasis appears to be the end product of the development of 'Herculean' cell clones capable of independent growth, invasion, adhesion, avoidance of apoptosis, and angiogenesis. Although significant progress has been made in understanding the sequential genetic events leading to the development of cancer, the precise genes and the associated molecular pathways underlying the development of metastatic potential are still poorly understood. Moreover, our enhanced genetic knowledge has had relatively little trickle down effect on our clinical management of this deadly disease. For this reason, we undertook a comprehensive study to develop a molecular encyclopedia of new tumor markers and markers of tumor progression, some of which will hopefully prove useful in the clinical management of colon cancer patients by means of their capacity to detect and predict the stage and disease burden. This review will focus on the application of gene expression profiling technology to the problem of identifying new tumor markers and progression markers, and the discovery of osteopontin as the leading candidate clinical marker derived from a screen of approximately 12,000 named genes.

Biomarkers, Tumor↗
PubMed2002

Induction of prostate apoptosis by alpha1-adrenoceptor antagonists: mechanistic significance of the quinazoline component.

alpha(1)-Adrenoceptor antagonists, have been documented to induce apoptosis and reduce prostate tumor vascularity in benign and malignant prostate cells. The quinazoline based alpha(1)-antagonists, doxazosin and terazosin but not tamsulosin (a sulphonamide derivative) suppress prostate growth without affecting cell proliferation. These quinazoline-mediated apoptotic effects occur via an alpha(1)-adrenoceptor independent mechanism potentially involving activation of the TGF-beta signal transduction pathway. This review discusses the current knowledge of the action of quinazoline-derived alpha(1)-adrenoceptor antagonists in the benign and malignant prostate and their potential therapeutic use in the treatment of benign prostatic hyperplasia (BPH) and prostate cancer. Finally, a molecular pathway is proposed for their observed apoptotic function against prostate cells. Increased understanding of the action of these established and clinically accepted agents would provide a basis for the design of safe, effective therapeutic regimens in the treatment of prostatic diseases.

Adrenergic Antagonists↗
PubMed2004

New B7 family members with positive and negative costimulatory function.

The B7 family of T-cell costimulatory molecules has expanded considerably in recent years. Among the new costimulatory molecules discovered are inhibitory and activating pathways. Both ligands and receptors often have multiple binding partners, adding to the complexity of T-cell regulation. Some B7 molecules also exhibit reverse signaling, affecting activation of both antigen-presenting cells and T cells. An increased understanding of these pathways of T-cell regulation results in promising new therapeutics because T-cell interference can be better targeted to specific states of activation or location. This will decrease side-effects such as systemic immunosuppression and increase efficiency. Targeting B7 molecular pathways for either inhibiting or increasing cell-mediated immunity has so far shown promising results in models of autoimmunity, transplant rejection and tumor immunotherapy.

Animals↗
PubMed2006

Microarray-based analysis of spinal versus intracranial meningiomas: different clinical, biological, and genetic characteristics associated with distinct patterns of gene expression.

It has long been recognized that spinal meningiomas show particular clinical and histological features. Here, we compare the clinico-biological characteristics as well as the genetic abnormalities and patterns of gene expression of spinal and intracranial meningiomas. Fourteen spinal and 141 intracranial meningioma patients were analyzed at diagnosis. In all tumors, interphase fluorescence in situ hybridization (iFISH) studies were performed for the detection of quantitative abnormalities for 11 different chromosomes. Additionally, microarray analyses were performed on a subgroup of 18 histologically benign meningiomas (7 spinal and 11 intracranial). Upon comparison with intracranial tumors, spinal meningiomas showed a marked predominance of psammomatous and transitional tumors (p = 0.001), together with a higher proportion of cases displaying a single tumor cell clone by iFISH (p = 0.004). In 86% of the spinal versus 56% of the intracranial tumors (p = 0.01), the ancestral tumor cell clone detected showed either absence of any chromosomal abnormality or monosomy 22/22q- alone. Analysis of gene expression profiles showed differential expression between spinal and intracranial meningiomas for a total of 1555 genes, 35 of which allowed a clear distinction between both tumor types. Most of these 35 genes (n = 30) showed significantly higher expression among spinal tumors and corresponded to genes involved in signal transduction pathways, which did not show a significantly different expression according to tumor histopathology. In summary, we show the occurrence of unique patterns of genetic abnormalities and gene expression profiles in spinal as compared to intracranial meningiomas that provide new insights into the molecular pathways involved in the tumorigenesis and progression of spinal meningiomas, and could help explain their particular clinical and histological features.

Aged↗
PubMed2001

PTHrP inhibits adipocyte differentiation by down-regulating PPAR gamma activity via a MAPK-dependent pathway.

We examined the capacity of PTHrP to modulate the terminal differentiation of the preadipocytic cell line, 3T3-L1. These cells express endogenous PTHrP and its receptor, but expression levels were undetectable after differentiation into mature adipocytes. Cells stably overexpressing PTHrP failed to differentiate when induced to undergo adipogenesis and proliferated at a faster rate. MAPK activity was elevated in PTHrP-transfected 3T3-L1 cells, and treatment with the PKA inhibitor H-8 decreased this activity. Inhibition of MAPK kinase with PD098059 permitted terminal differentiation of PTHrP-transfected 3T3-L1 cells to proceed. Although PPAR gamma gene expression levels remained relatively constant in the PTHrP-transfected cells, PPAR gamma phosphorylation was enhanced. Furthermore, the capacity of PPAR gamma to stimulate transcription in the presence of troglitazone was diminished by PTHrP. Expression of the PPAR gamma-regulated adipocyte specific gene aP2 transiently rose and then fell in PTHrP-transfected cells. These results indicate that PTHrP can increase MAPK activity in 3T3-L1 cells via the PKA pathway, thereby enhancing PPAR gamma phosphorylation. This modification can inactivate the transcriptional enhancing activity of PPAR gamma and diminish the expression of adipocyte-specific genes. These studies therefore demonstrate that PTHrP may inhibit the terminal differentiation of preadipocytes and describe a molecular pathway by which this action can be achieved.

3T3 Cells↗
PubMed2004

Pharmacogenomics and breast cancer.

Germline variants can be used to study breast cancer susceptibility as well as the variable response to both drug and radiation therapy used in the treatment of breast cancer. In addition to germline high-penetrance mutations important in familial and hereditary breast cancer, a substantial component of breast cancer risk can be attributed to the combined effect of many low-risk germline polymorphisms involved in relevant pathways like those of DNA repair, adhesion, carcinogen and estrogen metabolism. Additionally, the identification of sequence variants in genes involved in response to chemotherapy and radiation treatment, has created the opportunity to apply genomics to individualized treatment. The continued insight into the molecular pathways involved in drug and radiation response has enabled progress in tailoring therapies in such a way as to both maximize efficacy and minimize toxicity. Polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters and drug targets can be used to predict toxicity and response to pharmacologic agents used in breast cancer treatment. Similarly, germline variants in genes involved in DNA repair, radiation-induced fibrosis and reactive oxygen species may be used to predict response to radiation therapy. As a result, pharmacogenomics is rapidly evolving to affect the entire spectrum of breast cancer management, influencing both prevention and treatment choices.

Animals↗
PubMed2005

Inhibition of Rho kinase modulates radiation induced fibrogenic phenotype in intestinal smooth muscle cells through alteration of the cytoskeleton and connective tissue growth factor expression.

BACKGROUND: Late radiation enteritis in humans is associated with accumulation of extracellular matrix and increased connective tissue growth factor (CTGF) expression that may involve intestinal muscular layers. AIMS: We investigated the molecular pathways involved in maintenance of radiation induced fibrosis by gene profiling and postulated that alteration of the Rho pathway could be associated with radiation induced fibrogenic signals and CTGF sustained expression. PATIENTS AND METHODS: Ileal biopsies from individuals with and without radiation enteritis were analysed by cDNA array, and primary cultures of intestinal smooth muscle cells were established. Then, the effect of pharmacological inhibition of p160 Rho kinase, using Y-27632, was studied by real time reverse transcription-polymerase chain reaction, western blot, and electrophoretic mobility shift assay. RESULTS: Molecular profile analysis of late radiation enteritis showed alterations in expression of genes coding for the Rho proteins. To investigate further the involvement of the Rho pathway in intestinal radiation induced fibrosis, primary intestinal smooth muscle cells were isolated from radiation enteritis. They retained their fibrogenic differentiation in vitro, exhibited a typical cytoskeletal network, a high constitutive CTGF level, increased collagen secretory capacity, and altered expression of genes coding for the Rho family. Rho kinase blockade induced a simultaneous decrease in the number of actin stress fibres, alpha smooth muscle actin, and heat shock protein 27 levels. It also decreased CTGF levels, probably through nuclear factor kappaB inhibition, and caused decreased expression of the type I collagen gene. CONCLUSION: This study is the first showing involvement of the Rho/Rho kinase pathway in radiation fibrosis and intestinal smooth muscle cell fibrogenic differentiation. It suggests that specific inhibition of Rho kinase may be a promising approach for the development of antifibrotic therapies.

Actins↗
PubMed1999

Phenotypic determination of epithelial appendages: genes, developmental pathways, and evolution.

Epithelial appendages are derivatives of epithelia that elaborate to form specialized structures and functions. The appendage can protrude out, such as in teeth and feathers, or invaginate in, such as in glands. The epithelia can be ectodermal, such as in hairs, or endodermal, such as in livers. Using feather as a prototype of epithelial appendage, we study the molecular signals involved in the successive stages of epithelial-mesenchymal interactions during morphogenesis. We propose that these form the basics of gene networks, which can be integrated to gene supernetwork and totinetwork. Because the unit of development is molecular pathway rather than single molecule, and the unit of morphogenesis is cell group rather than single cell, we make the analogy between genes/developmental pathways and words/sentences. The study of developmental pathways in epithelial appendage organogenesis will help us to understand the grammar of genes and the basic rules in constructing regulated new growth. This knowledge may contribute to the study of cancer biology (deregulated new growth) and organ regeneration.

Animals↗
PubMed2005

Zebrafish as a model for myelopoiesis during embryogenesis.

Zebrafish produce nearly identical hematopoeitic cell lineages to those found in mammals and other higher vertebrates. As in mammals, blood cell development proceeds in distinct waves, constituting embryonic (primitive) and adult (definitive) hematopoiesis. The conservation of genes such as scl, pu.1, c/ebpalpha, mpo, l-plastin, and lysozyme C in myelopoiesis and the corresponding expression patterns in zebrafish suggests that shared genetic pathways regulate this complex developmental process. In the zebrafish model system, experimental approaches have been applied, including RNA in situ hybridization, morpholino injections, and the analysis of mutant and transgenic fish lines, leading to improved understanding of the regulation in vivo of key molecular pathways with conserved roles in vertebrate myelopoiesis.

Animals↗