ISSN:0892-6638    

DOI:10.1096/fasebj.6.15.1464367

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

The gene encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCK) is expressed in multiple cell types in diverse tissues including liver, kidney, intestine, and white and brown adipose tissues. It can thus be considered a model system for examining the regulation of cell‐specific transcription. The PEPCK gene is transcribed from a single start site, but studies of transgenic mice have revealed that distinctcis‐acting elements (and thus differenttrans‐acting factors) regulate PEPCK expression in hepatocytes, renal proximal tubule epithelial cells, and adipocytes. Hepatocytes require elements between –457 and +69 bp; renal proximal tubule epithelia require elements between –363 and +69 bp; and adipocytes require elements between –2086 and –888 bp. An additional element downstream of +69 bp is required to either attenuate PEPCK mRNA levels in liver and fat or increase renal PEPCK mRNA. We hypothesize that the transcription factors C/EBP and DBP are the principal tissue‐specific regulators in liver, and that HNF‐1 and perhaps C/EBP are important for kidney‐specific PEPCK expression. We propose that the putative downstream element is involved in regulating PEPCK mRNA turnover in liver and fat. Finally, we suggest that the fat‐specific element is an enhancer that requires a novel adipogenic regulatory factor, ARF6, to function. The long‐term objective will be to fine map the cis‐acting elements and identify the cognatetrans‐acting factors that regulate PEPCK in liver, kidney and fat. This information will help elucidate the combinatorial mechanisms that control the cell‐specific expression of this complex gene.— Beale, E. G., Clouthier, D. E., Hammer, R. E. Cell‐specific expression of cytosolic phosphoenolpyruvate carboxykinase in transgenic mice.FASEB J. 6: 3330‐3337; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.15.1281456

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

Excitotoxicity refers to neuronal cell death caused by activation of excitatory amino acid receptors. A substantial body of evidence has implicated excitotoxicity as a mechanism of cell death in both acute and chronic neurologic diseases. A major recent advance has been the successful cloning and expression of theN‐methyl‐d‐aspartate (NMDA), non‐NMDA, and metabotropic glutamate receptors. The cellular mechanisms responsible for cell death after activation of these receptors are still being clarified. In acute neurologic diseases such as stroke and head trauma, excitotoxicity may be related to excessive glutamate release. In chronic neurodegenerative diseases, however, a slow excitotoxic process is more likely to occur as a consequence of either a receptor abnormality or an impairment of energy metabolism. Recent therapeutic studies have demonstrated the efficacy of non‐NMDA receptor antagonists in experimental studies of global ischemia.— Beal, M. F. Mechanisms of excitotoxicity in neurologic diseases.FASEB J.6: 3338‐3344; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.15.1464368

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

α2‐macroglobulin (α2M) and related proteins share the function of binding host or foreign peptides and particles, thereby serving as humoral defense barriers against pathogens in the plasma and tissues of vertebrates. In humanα2M, several reactive sites including high‐affinity sites for zinc, transglutaminase cross‐linking sites, and reactive sites derived from the activated thiol ester can mediate reversible or irreversible capture of proteins of diverse biological functions.α2M interacts and captures virtually any proteinase whether self or foreign, suggesting a function as a unique “panproteinase inhibitor.” Activation ofα2M generates novel binding sites, which mediate complex formation with cytokines and other peptides. Direct evidence of physical association of cytokines with activatedα2M indicated its role as biological response modifier in cell cultures. A mechanism commonly referred to as “clearance of activatedα2M” involves C a2+‐dependent binding to a specific cell surface receptor, a member of the low‐density lipoprotein receptor supergene family, that mediates cellular uptake by endocytosis and delivery to endosomes and lysosomes. The peptide binding function ofα2M, therefore, may also be viewed as a mechanism that allows targeting of biologically active peptides to different cell types expressing theα2M receptor. Internalized complexes may be dispatched into different pathways of endocytic/lysosomal pathways in a cell type‐specific manner. In addition, bioactive peptides bound toα2M may dissociate in the process of intracellular ligand sorting, thereby modulating cell function, or remain bound and share the catabolic fate ofα2M. The diversified and probably programmed binding functions ofα2M indicate that in addition to its role in trapping proteinases, it has other biological activities that remain to be fully defined. Thatα2M may function as a binding and carrier protein with targeting characteristics is predicted from1) the known functions ofα2M, and2) the similarity of the fate ofα2M with proteins whose significance in targeting and intracellular trafficking has been studied in more detail.— Borth, W.α2‐Macroglobulin, a multifunctional binding protein with targeting characteristics.FASEB J.6: 3345‐3353; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.15.1281457

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

Transcription requires the recognition of numerous DNA sequences by diverse transcription factors, which together assemble large nucleoprotein complexes that tether RNA polymerase and facilitate the initiation of RNA synthesis. In vivo the assembly of these transcription complexes occurs in a nuclear environment where the template DNA is compacted more than 105‐fold through the assembly of chromatin. Our current knowledge of chromatin structure raises the major issues of the accessibility of DNA to both transcription factors and RNA polymerase and of the progression of RNA polymerase along the chromatin fiber. Novel genetic and biochemical approaches have established that specific chromatin structures have a major impact on the transcription process. Precise alterations in histone sequence, nucleosome structure, and folding of the chromatin fiber influence both the activation and repression of genes. These results offer substantial insight into the role of modulations in chromosome structure during vertebrate development. Transcription factors, histones, and the organization of DNA within the chromosome are intimately linked, and only when the correct framework is assembled can they function together to achieve correct genetic regulation.— Wolffe, A. P. New insights into chromatin function in transcriptional control.FASEB J.6: 3354‐3361; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.15.1464369

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

Since 1989, the receptors for fibroblast growth factors (FGFs) were cloned and characterized as a subgroup of the family of receptor tyrosine kinases. Four FGF receptor genes were identified, all of which encode membrane‐bound glycoproteins containing three immunoglobulin (Ig) ‐like domains at the extracellular region, where only two of these domains are involved in ligand binding. Three unique features characterize the FGF receptors:1) overlapping recognition and redundant specificity, where one receptor may bind with a similar affinity several of the seven known FGFs and one FGF may bind similarly to several distinct receptors.2) The binding of FGFs to their receptors is dependent on the interaction of FGF with cell surface heparan sulfate proteoglycans.3) A multitude of isoforms of cell‐bound or secreted receptors are produced by the same gene. The gene structure of these receptors revealed two major mechanisms that are responsible for the formation of the diverse forms: alternative mRNA splicing, resulting in deletions or alternate exons usage, and internal polyadenylation, resulting in truncated products. These are reminiscent of mechanisms that also operate in the immunoglobulin family to generate diversity and to produce either secreted or cell‐bound molecules. Tissue‐specific alternative splicing in FGF receptors allows for the generation of two distinct receptors from a single gene because alternative exons determine the sequence of the COOH‐terminal half of the third Ig‐like domain involved in ligand binding. This represents a novel genetic mechanism to generate receptor diversity and specificity and to increase receptor repertoire.— Givol, D.; Yayon, A. Complexity of FGF receptors: genetic basis for structural diversity and functional specificity.FASEB J.6: 3362‐3369; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.15.1464370

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

T cells recognize antigen in the form of a peptide associated with a cell surface molecule encoded by the major histocompatibility gene complex (MHC). The elaborate requirements for the T cell receptor (TCR)‐antigen interaction stand in contrast to the simple and defined nature of the antigenic determinants recognized by antibodies. The similarity in the molecular structure and gene organization between antibodies and the TCR has prompted attempts to interchange the antigen‐binding, variable regions of these molecules. To this end, chimeric TCR (cTCR) genes, composed of the variable domains of antibodies linked to TCR constant regions, have been used to confer antibody‐type specificity on T cells. cTCR‐expressing T cells respond to stimulator cells as well as to immobilized antigen in an MHC unrestricted and independent manner. The antibody‐like specificity of the resulting T cells has been exploited, using defined ligands, to elucidate the physicochemical parameters that govern TCR‐mediated signaling, and to provide a useful experimental system to study the role of MHC and cell‐adhesion/accessory molecules in T cell activation. The successful expression of such cTCR in transgenic mice opens new avenues to explore the role of the MHC in T cell development and maturation. Eventually, chimeric receptors specific to tumor or viral antigens might be used for in vivo targeting of T cells in the framework of immuno‐ and gene therapy.— Gross, G.; Eshhar, Z. Endowing T cells with antibody specificity using chimeric T cell receptors.FASEB J.6: 3370‐3378; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.15.1464371

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

l‐Carnitine has been described as a “conditionally essential” nutrient for humans. Segments of the human population suggested as having a requirement for carnitine include infants (premature and full‐term), patients on long‐term parenteral nutrition, and perhaps children. The evidence to support these claims includes1) low circulating carnitine concentrations;2) abnormal (or at least different) circulating metabolite concentrations (free fatty acids, triglycerides, ketone bodies), and3) very limited and inconsistent growth data. A number of subjective observations and anecdotal case reports have been offered in support of a requirement for carnitine. Exogenous carnitine is required to maintain “normal” (in the epidemiologic sense) plasma or serum carnitine concentrations in humans of all ages. But “functional carnitine deficiency,” defined by abnormal clinical presentation correctable by carnitine administration, has not been demonstrated in an otherwise normal (nonpathologic) population. On the other hand, nutritional or pharmacological intervention with carnitine or its esters may be beneficial for very premature infants, infants and children with various clinical conditions associated with low circulating carnitine concentrations, and in some chronic diseases associated with the aging process.— Rebouche, C. J. Carnitine function and requirements during the life cycle.FASEB J.6: 3379‐3386; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.15.1464372

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

Most of the recently cloned cytokine receptors that operate in the immune and hematopoietic systems contain no tyrosine kinase domains in their cytoplasmic regions, unlike the family of growth factor receptors defined earlier. However, they can be assigned to several new types of receptor families based on structural similarities among them. It is characteristic of these receptors that many of them require a receptor‐associated molecule in order to achieve high‐affinity ligand binding and/or transmission of cytoplasmic signals. Receptor‐associated molecules have been found that transduce cytoplasmic signals and are shared by different cytokine receptors. Phosphorylation of the receptors and of various cytoplasmic proteins after ligand stimulation seems to be a common event in cytokine systems. Insight into the pleiotropic and redundant nature of cytokine action is provided by the discovery of several new cytokine receptor families and of shared signal transduction molecules and by the idea that several cytoplasmic kinases may be able to functionally substitute for one another in transmitting cytokine signals.— Taga, T., Kishimoto, T. Cytokine receptors and signal transduction.FASEB J.7: 3387‐3396; 1993.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.15.1334470

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

Hydrophobic organization: Determination of the structure of the bacterial photosynthetic reaction center, bacterial porins, and bacteriorhodopsin allows a comparison of the basic structural features of integral membrane proteins. Structure parameters of membrane‐ and water‐soluble proteins are surprisingly similar, given the different dielectric environments, except for the polarity of residues on the protein surface.Hydrophobic and electrostatic forces: 1) Intramembrane helix‐helix interactions that are sensitive to small structure changes can dictate assembly of membrane proteins, as indicated by reconstitution of bacteriorhodopsin from proteolytic fragments and specific dimer formation of the human erythrocyte sialoglycoprotein glycophorin A.2) Electrostatic interactions have an important role in determining thetrans‐membrane orientation of integral membrane proteins of the bacterial inner membrane, as expressed by the “positive‐inside” rule for the distribution of basic residues on thecisrelative to thetransside of the membrane‐spanningα‐helices. The use of this charge asymmetry rule, in conjunction with a hydrophobicity algorithm for prediction of membrane‐spanning domains, allows accurate prediction of the folding patterns of such polypeptides across the membrane. A role of electrostatic interactions in assembly and maintenance of the structure of oligomeric integral membrane protein complexes is also implied by the separation and extrusion from the membrane, at high pH, of the major hydrophobic sub‐units of the cytochromeb6fcomplex from the chloroplast thylakoid membrane. It is inferred that the hydrophobic helix‐helix interactions between the subunits of this complex, whose function is electron transfer and proton translocation, are relatively weak compared to those in bacteriorhodopsin.— Cramer, W. A., Engelman, D. M., von Heijne, G, Rees, D. C. Forces involved in the assembly and stabilization of membrane proteins.FASEB J.6: 3397‐3402; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.15.1464373

出版商:Wiley    

年代:1992

数据来源: WILEY