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At least 1,297 records · Page 72Linked to original sources
PubMed1995

The C/EBP family of transcription factors.

The C/EBP proteins form a family of transcription factors with at least seven members. These proteins consist of three structural components which include a C-terminal leucine-zipper, a basic DNA-binding region and a N-terminal transactivating region. Dimerization through the leucine-zipper leads to formation of homo- and heterodimers which then bind with their two basic regions to often non-symmetric DNA-sequences in the promoter/enhancer regions of a variety of genes. Expression of C/EBP is prominent in adipocytes, hepatocytes and monocytes/macrophages, and here these proteins are involved in tissue-specific gene expression. Target genes for C/EBP include those for acute phase response genes in liver cells and for cytokine genes in monocytes/macrophages. Therefore, intervention at the level of C/EBP transcription factors may prove effective in controlling immune response.

Animals↗
PubMed2003

Structural genomics of Mycobacterium tuberculosis: a preliminary report of progress at UCLA.

The growing list of fully sequenced genomes, combined with innovations in the fields of structural biology and bioinformatics, provides a synergy for the discovery of new drug targets. With this background, the TB Structural Genomics Consortium has been formed. This international consortium is comprised of laboratories from 31 universities and institutes in 13 countries. The goal of the consortium is to determine the structures of over 400 potential drug targets from the genome of Mycobacterium tuberculosis and analyze their structures in the context of functional information. We summarize the efforts of the UCLA consortium members. Potential drug targets were selected using a variety of bioinformatics methods and screened for certain physical and species-specific properties to yield a starting group of protein targets for structure determination. Target determination methods include protein phylogenetic profiles and Rosetta Stone methods, and the use of related biochemical pathways to select genes linked to essential prokaryotic genes. Criteria imposed on target selection included potential protein solubility, protein or domain size, and targets that lack homologs in eukaryotic organisms. In addition, some protein targets were chosen that are specific to M. tuberculosis, such as PE and PPE domains. Thus far, the UCLA group has cloned 263 targets, expressed 171 proteins and purified 40 proteins, which are currently in crystallization trials. Our efforts have yielded 13 crystals and eight structures. Seven structures are summarized here. Four of the structures are secreted proteins: antigen 85B; MPT 63, which is one of the three major secreted proteins of M. tuberculosis; a thioredoxin derivative Rv2878c; and potentially secreted glutamate synthetase. We also report the structures of three proteins that are potentially essential to the survival of M. tuberculosis: a protein involved in the folate biosynthetic pathway (Rv3607c); a protein involved in the biosynthesis of vitamin B5 (Rv3602c); and a pyrophosphatase, Rv2697c. Our approach to the M. tuberculosis structural genomics project will yield information for drug design and vaccine production against tuberculosis. In addition, this study will provide further insights into the mechanisms of mycobacterial pathogenesis.

Bacterial Proteins↗
PubMed1998

Two transgenic approaches to define the cell lineages in endocrine pancreas development.

Ontogenic relationships between the different endocrine cell types of the islets of Langerhans were explored by generating transgenic mice, in which cells transcribing the glucagon, insulin, or pancreatic polypeptide genes were destroyed through the promoter-targeted expression of the diphtheria toxin A chain. In an alternate approach, to assess whether insulin cells are derived from precursors producing glucagon or PP, transgenic mice were generated bearing an insulin promoter-driven, and loxP-containing ('floxed') reporter transgene that can be irreversibly 'tagged' by recombination. They were crossed with mice expressing another transgene ('tagger') encoding Cre (cyclization recombination) recombinase in either glucagon or PP cells. The results obtained using both approaches indicate that neither glucagon nor insulin gene-expressing cells are the precursors to the other islet cells; also, they suggest that PP gene-expressing cells are necessary for the differentiation of islet insulin and somatostatin cells, through a cell lineage or a paracrine relationship.

Animals↗
PubMed2001

Stereotactic radiosurgery in the management of angiographically occult vascular malformations.

PURPOSE: To evaluate the role of stereotactic radiosurgery in the treatment of angiographically occult vascular malformations (AOVMs). METHODS AND MATERIALS: From 1987 to 1996, 21 patients, 10 males and 11 females, median age of 41 years (range: 7-75 years), with an intracerebral AOVM underwent stereotactic radiosurgery at our institution. All were considered at high risk for surgical intervention. The vascular lesions were located in the brainstem (17 patients), basal ganglia (2), occipital lobe (1), and cerebellum (1). Diagnosis was based on high-resolution magnetic resonance imaging (MRI). Clinical presentation at onset included previous intracerebral hemorrhage (20 patients) and epilepsy (1). All patients were treated with a linac-based radiosurgical technique. The median dose delivered was 25 Gy (range 13-50 Gy), typically prescribed to the 80-90% isodose surface (range 50-90%), which corresponded to the periphery of the vascular malformation. Patients were followed by clinical neurologic assessment and by MRI on a regular interval basis. RESULTS: Follow-up was obtained in 20 patients; clinical or MRI information was not available for 1 patient, and this patient was excluded from our analysis. At a median follow-up of 77 months (range: 4-141 months), follow-up MRIs postradiosurgery do not demonstrate any changes in the appearance of the AOVM. Four patients developed an intracranial bleed at 4, 8, 35, and 57 months postradiosurgery. Annual hemorrhage rates were considerably higher in the observation period preradiosurgery than postradiosurgery (30% vs. 3.2%, p < 0.001). Complications postradiosurgery were observed in 4 patients. Three patients developed mild to moderate edema surrounding the radiosurgical target, expressed at 5, 8, and 24 months, respectively. In all cases, the edema was transient and resolved completely on subsequent MRIs. One of the 4 patients developed radiation necrosis 8 months after radiosurgery. CONCLUSION: The use of stereotactic radiosurgery in the treatment of AOVM continues to be controversial. Our results appear to show a reduction in the risk of symptomatic hemorrhage post treatment. Patients with previous history of hemorrhage or progressive neurologic deficit and small, well circumscribed lesions may benefit from a trial of stereotactic radiosurgery.

Adolescent↗
PubMedDate not supplied

Selection of the T-cell repertoire during ontogeny.

This report examines conflicting hypotheses concerning T-cell repertoire selection in terms of H-2 restriction during ontogeny. The experiments described in this report were incompatible with the hypothesis that bias in the repertoire is solely a consequence of "more or less intentional priming" by foreign antigen. Rather, results indicate that the repertoire is selected by self major histocompatibility complex (MHC) antigens in the absence of foreign antigens. Allorestricted T cells, the existence of which was previously thought to be incompatible with the concept of complete repertoire selection by self MHC antigens, were shown to significantly cross-react on targets expressing self MHC antigens. Thus, it is possible that allorestricted T cells are simply cross-reactive T-cell clones restricted by self MHC antigens; indeed, all experimental data were compatible with the idea of complete selection of the T-cell repertoire in terms of H-2 restriction by self MHC antigens.

Animals↗
PubMed2001

Kinase-independent requirement of EphB2 receptors in hippocampal synaptic plasticity.

During development, Eph receptors mediate the repulsive axon guidance function of ephrins, a family of membrane attached ligands with their own receptor-like signaling potential. In cultured glutamatergic neurons, EphB2 receptors were recently shown to associate with NMDA receptors at synaptic sites and were suggested to play a role in synaptogenesis. Here we show that Eph receptor stimulation in cultured neurons modulates signaling pathways implicated in synaptic plasticity, suggesting cross-talk with NMDA receptor-activated pathways. Mice lacking EphB2 have normal hippocampal synapse morphology, but display defects in synaptic plasticity. In EphB2(-/-) hippocampal slices, protein synthesis-dependent long-term potentiation (LTP) was impaired, and two forms of synaptic depression were completely extinguished. Interestingly, targeted expression of a carboxy-terminally truncated form of EphB2 rescued the EphB2 null phenotype, indicating that EphB2 kinase signaling is not required for these EphB2-mediated functions.

Age Factors↗
PubMed2002

Temporal control of glial cell migration in the Drosophila eye requires gilgamesh, hedgehog, and eye specification genes.

In the Drosophila visual system, photoreceptor neurons (R cells) extend axons towards glial cells located at the posterior edge of the eye disc. In gilgamesh (gish) mutants, glial cells invade anterior regions of the eye disc prior to R cell differentiation and R cell axons extend anteriorly along these cells. gish encodes casein kinase Igamma. gish, sine oculis, eyeless, and hedgehog (hh) act in the posterior region of the eye disc to prevent precocious glial cell migration. Targeted expression of Hh in this region rescues the gish phenotype, though the glial cells do not require the canonical Hh signaling pathway to respond. We propose that the spatiotemporal control of glial cell migration plays a critical role in determining the directionality of R cell axon outgrowth.

Animals↗
PubMed2003

Drug resistance reversal--are we getting closer?

Clinical drug resistance is a major barrier to overcome before chemotherapy can become curative for most patients presenting with metastatic cancer. Rational attempts to tackle clinical drug resistance need to be based on an understanding of the mechanisms involved; these are likely to be complex and multifactorial, and may be due to inadequate drug exposure or alterations in the cancer cell itself. This article reviews a number of strategies used to tackle drug resistance, focussing on work in our institution related to the treatment of ovarian cancer and resistance to platinum and taxane-based chemotherapy. Further progress towards drug resistance reversal will require a three-pronged approach, namely: the development of novel cytotoxics which exploit selectively expressed targets; modulation of resistance to conventional agents and, most importantly, a serious attempt to understand resistance mechanisms in tumour samples taken both pre- and post-chemotherapy.

Antineoplastic Agents↗
PubMedDate not supplied

split ends, a new component of the Drosophila EGF receptor pathway, regulates development of midline glial cells.

Signaling by DER, the Drosophila epidermal growth factor receptor tyrosine kinase (RTK), is essential for proper migration and survival of midline glial cells (MGCs) in the embryonic central nervous system (CNS) [1-4]. We recently isolated a gene called split ends (spen) in a screen designed to identify new components of the RTK/Ras pathway [5]. Drosophila Spen and its orthologs are characterized by a distinct set of RNA recognition motifs (RRMs) and a SPOC domain, a highly conserved carboxy-terminal domain of unknown function [5-7]. To investigate spen function in the context of RTK signaling, we examined the consequences of spen loss-of-function mutations on embryonic CNS development. We found that spen was required for normal migration and survival of MGCs and that embryos lacking spen had CNS defects strikingly reminiscent of those seen in mutants of several known components of the DER signaling pathway. In addition, spen interacted synergistically with the RTK effector pointed. Using MGC-targeted expression, we found that increased Ras signaling rescued the lethality associated with expression of a dominant-negative spen transgene. Therefore, spen encodes a positively acting component of the DER/Ras signaling pathway.

Animals↗
PubMed2002

Peripheral blood stem cell mobilization. A role for CXC chemokines.

Chemokines induce rapid hematopoietic stem and progenitor cell mobilization and synergize with hematopoietic cytokines in mobilizing stem and progenitor cells. These proteins alone and in combination offer new paradigms for autologous and allogeneic peripheral blood stem cell transplantation (PBSCT). The mechanisms responsible for hematopoietic stem cell (HSC) mobilization either with growth factors or chemokines are largely unknown, but a better understanding of these mechanisms will permit the development of novel, more rapid and efficacious regimens. Studies presented herein indicate that the CXCR2 chemokine receptor that interacts with selective chemokine ligands, particularly GRObeta/CXCL2 and GRObeta-T, may be the dominant receptor mediating hematopoietic cell mobilization, and that polymorphonuclear neutrophils may be the primary CXCR2 expressing target cell for stem and progenitor cell mobilization.

Animals↗
PubMed2003

Molecular biology and gene therapy in the treatment of chronic pain.

Technologic advancements have made cell type-specific targeting, expression control, and safe and stable gene transfer possible. Animal research has provided increasing experience with gene transfer to the nervous system and sensory neurons in particular. Gene-based neuromodultion can be achieved through neuronal delivery of transgenes capable of altering synaptic function. Alternatively, ex vivo gene transfer can be used to create cell lines capable of secreting analgesic neurepeptides. Translatation of these grafts and direct gene-based neuromoduation can be applied to the control of pain and the root causes of pain. These approaches combine anatomic and pharmacologic specificity. As the technology continues to improve, clinical application of cellular and molecular pain control is likely.

Animals↗
PubMed2003

Identification of MHC class II-restricted tumor antigens recognized by CD4+ T cells.

CD4+ T cells play a central role in orchestrating host immune responses against cancer as well as autoimmune and infectious diseases. Identification of major histocompatibility complex (MHC) class II-restricted helper T peptides is important for development of effective vaccines. The lack of effective methods to identify such T-cell peptides is a major hurdle in the use of antigen-specific CD4+ T cells in cancer vaccines. Here we describe a genetic targeting expression system for cloning genes encoding for MHC class II-restricted tumor antigens recognized by tumor-reactive CD4+ T cells. Helper T peptides are subsequently identified by using synthetic peptides to test their ability to stimulate CD4+ T cells.

Antigens, Neoplasm↗
PubMed2002

Aberrations in the MTS1 tumor suppressor locus in oral squamous cell carcinoma lines preferentially affect the INK4A gene and result in increased cdk6 activity.

The signal transduction pathway regulated by the retinoblastoma tumor suppressor protein, pRB, is abrogated in the majority of human cancers. Using a series of cell lines derived from oral squamous cell carcinomas (SCCs) that were not subjected to radiation or chemotherapy treatment, we detected specific hyperactivity of cyclin dependent kinase (cdk) 6 but not cdk4. Subcellular localization studies showed a predominant nuclear localization of cdk6, demonstrating that this kinase was biologically active. The molecular basis for this aberration are mutations in the MTS1 locus of chromosome 9p21. This locus encodes two partially overlapping genes, the cdk inhibitor p16(ink4a), and p14(ARF), an inhibitor of mdm2-mediated degradation of p53. Our analysis demonstrates that the mutations of the MTS1 locus in oral SCC specifically target expression of the p16(ink4a) gene but less frequently affect p14(ARF). These results suggest that hyperactivity of cdk6 represents a distinct mechanism for pRB inactivation in oral SCC.

Carcinoma, Squamous Cell↗
PubMed1995

Biotechnology domain.

Biotechnology and the use of biologically based agents for the betterment of mankind is an active field which is founded on the interaction between many basic sciences. This is achieved in coordination with engineering and technology for scaling up purposes. The application of modern recombinant DNA technology gave momentum and new horizons to the field of biotechnology both in the academic setting and in industry. The applications of biotechnology are being used in many fields including agriculture, medicine, industry, marine science and the environment. The final products of biotechnological applications are diverse. In the medical applications of biotechnology, for example, the field has been evolving in such a way that the final product could be a small molecule (e.g. drug/antibiotic) that can be developed based on genetic information by drug design or drug screening using a cloned and expressed target protein.

Animals↗
PubMed2002

Recent advances in understanding the mechanisms of TCDD immunotoxicity.

TCDD is a highly immunosuppressive chemical that induces potent suppression of immune responses in laboratory animals. However, apart from the requisite role of the AhR and the identification of bone-marrow-derived cells as critical AhR-expressing targets, the specific cells and the underlying biochemical mechanisms by which TCDD disrupts immunological functions remain unclear. Recent data suggest that a new paradigm for the mechanism of immunotoxic action of TCDD may be more accurate, moving from one focused on the suppression of immune functions to one focused on the inappropriate activation of cells, leading to anergy or death, and the consequent premature termination of the immune response. Enhanced activation of B cells, DC and CD4+ T cells by TCDD has been described as well as the earlier disappearance of the latter two populations from peripheral lymphoid organs. Although much remains to be learned about how inappropriate cellular activation via the AhR induces immune suppression, deducing this mechanism of action and the signaling pathways involved, should lead to new insight into basic mechanisms of immune regulation.

Animals↗
PubMed2000

Behavioral characterization and genetic analysis of the Drosophila melanogaster larval response to light as revealed by a novel individual assay.

A new assay was designed, named checker, that measures the individual response to light in the fruitfly Drosophila melanogaster larva. In this assay the Drosophila larva apparently modulates its pattern of locomotion when faced with a choice between a dark and lit environment by orienting its movement towards the dark environment. We show that, in this assay, a response to light can be measured as an increase in residence time in the dark versus the lit quadrant. Mutations that disrupt phototransduction in the adult Drosophila abolish the larval response to light, demonstrating that this larval visual function is similar to that of the adult fly. Similarly, no response to light was detected in strains where the larval visual system (photoreceptors and target area) was disrupted by a mutation in the homeobox containing gene sine oculis (so) gene. Ablation of photoreceptors by the targeted expression of the cell death gene hid under the control of the photoreceptor-specific transcription factor glass (gl) abolishes this response entirely. Finally, we demonstrate that this response to light can be mediated by rhodopsins other than the blue absorbing Rh1.

Animals↗
PubMed2001

Selection and orientation of adjacent genes influences DAM-mediated male sterility in transformed maize.

Anther-targeted expression of E. coli DNA (Adenosine-N6-)-Methyltransferase (DAM) in maize was tested as a means to produce male-sterile plants. A high frequency of male-sterile plants with reduced anther size was observed when DAM was regulated by the maize anther-specific promoter 5126 (5126:DAM) and placed upstream of the herbicide resistance gene, pat, regulated by the cauliflower mosaic virus (CaMV) 35S promoter (35S:PAT). In contrast, placement of 5126:DAM upstream of a pat gene regulated by either the maize ubiquitin (UBI:PAT) or rice actin (rACTIN:PAT) promoters resulted in male-fertile plants. Based on these observed differences, DAM-mediated sterility was used as a phenotypic marker to assess the contribution of factors affecting gene expression such as orientation of the transcription units, choice of regulatory sequences mediating expression of adjacent genes, and effects of varying the anther-specific promoter regulating DAM. Constructs that place a portion of the CaMV 35S promoter, including the native AS-1 sequences, between 5126:DAM and UBI:PAT yielded a high frequency of male-sterile plants with reduced anther size. Significant differences in the frequency of male-sterile events and the associated anther size were also observed when the position of 35S:PAT was changed relative to 5126:DAM. These data provide evidence that gene expression in transformed maize plants can be impacted by simply altering the order, orientation or regulatory sequences of adjacent genes.

Acetyltransferases↗
PubMed1999

A LIM-homeodomain combinatorial code for motor-neuron pathway selection.

Different classes of vertebrate motor neuron that innervate distinct muscle targets express unique combinations of LIM-homeodomain transcription factors, suggesting that a combinatorial code of LIM-homeodomain proteins may underlie the control of motor-neuron pathway selection. Studies of LIM-homeodomain genes in mouse, Drosophila melanogaster and Caenorhabditis elegans have revealed functions of these genes in neuronal survival, axon guidance, neurotransmitter expression and neuronal function, but, to our knowledge, none of these studies have addressed the issue of a functional code. Here we study two members of this gene family in Drosophila, namely lim3, the homologue of the vertebrate Lhx3 and Lhx4 genes, and islet, the homologue of the vertebrate Isl1 and Is12 genes. We show that Drosophila lim3 is expressed by a specific subset of islet-expressing motor neurons and that mutating or misexpressing lim3 switches motor-neuron projections predictably. Our results provide evidence that lim3 and islet constitute a combinatorial code that generates distinct motor-neuron identities.

Amino Acid Sequence↗