bluuebunny/crossref_metadata_2025 huggingface dataset:
Poliovirus translation: A paradigm for a novel initiation mechanism
Authors: Sonenberg Nahum , Pelletier Jerry
Published: February 2005

All eukaryotic cellular mRNAs, and most viral mRNAs, are blocked at their 5′ ends with a cap structure (m7GpppX, where × is any nucleotide). Poliovirus, along with a small number of other animal and plant viral mRNAs, does not contain a 5′ cap structure. Since the cap structure functions to facilitate ribosome binding to mRNA, translation of poliovirus must proceed by a cap‐independent mechanism. Consistent with this, recent studies have shown that ribosomes can bind to an internal region within the long 5′ noncoding sequence of poliovirus RNA. Possible mechanisms for cap‐independent translation are discussed. Cap‐independent translation of poliovirus RNA is of major importance to the mechanism of shut‐off of host protein synthesis after infection. Moreover, it is likely to play a role in determining poliovirus neurovirulence and attenuation.
A spontaneous sarcoma dependent on host tumor‐specific immune lymphocytes
Authors: Katz Jonathan D. , Bonavida Benjamin
Published: February 2005

The immune surveillance theory postulates that spontaneous tumors are normally rejected by the immune system and appear only when they override host‐immune recognition and rejection mechanisms. The present mini‐review describes a spontaneous tumor system, the reticulum cell sarcomas (RCS) in SJL/J mice, that is dependent on host tumor‐specific immune lymphocytes for growth. This continuous tumor‐specific response results in tumor progression and death of the host. This tumor system contradicts the basic concept of immune surveillance. We propose as an explanation that some highly antigenic tumors, like the RCS, may have evolved in a non‐autonomous fashion but, nevertheless, have lost regulatory controls of cell proliferation. In the RCS system, the tumor expresses Class II MHC I‐E like specificities that are not expressed on the host cells and which selectively stimulate a subpopulation of I‐E specific T cells, the Vβ17a+ clonotype, leading to their expansion and continuous nurturing of the tumor via secreted lymphokines. This neoantigenic stimulation bypasses the tumor regulatory response that might have resulted if the tumor had not expressed neo‐antigens. Furthermore, passive administration of anti‐clonotypic antibody to tumor‐bearing mice results in tumor regression and long‐term survival through removal of the tumor reactive T cells. Thus, in this tumor system, immunosuppressive treatments are the prescription for tumor rejection.
Functional and dynamic aspects of the mammalian nucleolus
Authors: Scheer Ulrich , Benavente Ricardo
Published: February 2005

Nucleoli are the sites of ribosome biogenesis. Transcription of the ribosomal RNA genes as well as processing and initial packaging of their transcripts with ribosomal and non‐ribosomal proteins all occur within the nucleolus in an ordered manner and under defined topological conditions. Components of the nucleolus have been localized by immunocytochemistry and their functional aspects investigated by microinjection of antibodies directed against the enzyme responsible for rDNA transcription, RNA polymerase I. The role of nascent transcripts in postmitotic formation of nucleoli will be discussed.
Calmodulin‐dependent protein kinase II
Authors: Fujisawa Hitoshi
Published: February 2005

Three multifunctional protein kinases, cyclic AMP‐dependent protein kinase, protein kinase C, and calmodulin‐dependent protein kinase II, are involved in signal transduction in response to their respective second messengers, cyclic AMP, diacylglycerol, and Ca2+. This review will summarize the key findings on calmodulin‐dependent protein kinase II.
The regulation of DNA repair during development
Authors: Mitchell David L. , Hartman Philip S.
Published: February 2005

DNA repair is important in such phenomena as carcinogenesis and aging. While much is known about DNA repair in single‐cell systems such as bacteria, yeast, and cultured mammalian cells, it is necessary to examine DNA repair in a developmental context in order to completely understand its processes in complex metazoa such as man. We present data to support the notion that proliferating cells from organ systems, tumors, and embryos have a greater DNA repair capacity than terminally differentiated, nonproliferating cells. Differential expression of repair genes and accessibility of chromatin to repair enzymes are considered as determinants in the developmental regulation of DNA repair.
Processing of recombination intermediates in vitro
Authors: West Stephen C.
Published: February 2005

Genetic recombination involves the exchange of genetic material between chromosomes to produce new assortments of alleles. As such, it affects one of the most fundamental and important components of heredity – the genome itself. To understand the molecular basis of recombination, efforts have been directed to try to determine how simple organisms recombine their DNA. One approach involves the development of in vitro systems in which recombination reactions can be studied using purified enzymes. Detailed studies of these systems, using enzymes isolated from bacteria and bacterial viruses, indicate the formation of unique protein‐DNA complexes. The structure of the DNA within these complexes has important consequences for the subsequent formation of recombinant products.
Dissecting the complexity of the nervous system by enhancer detection
Authors: Bellen Hugo J. , Wilson Clive , Gehring Walter J.
Published: February 2005

Enhancer detectors are DNA constructs which, when introduced into a eukaryotic genome, respond to nearby genomic transcriptional regulatory elements by means of a reporter gene, revealing the expression pattern of genes in their vicinity. Recent experiments in Drosophila suggest that enhancer detection is a powerful method to identify genes that are expressed in the nervous system. Since enhancer detectors allow a rapid molecular and genetic characterization of genes in their vicinity, the method will greatly facilitate the study of neural development and behavior.
Telomeres, telomerase and senescence
Authors: Greider Carol W.
Published: February 2005

Eukaryotic chromosomes end with tandem repeats of simple sequences. These GC rich repeats allow telomere replication and stabilize chromosome ends. Telomere replication involves an equilibrium of sequence loss and addition at the ends of chromosomes. Repeats are added de novo by telomerase, an unusual DNA polymerase. Telomerase is an RNP in which an essential RNA component provides the template for the added telomere repeats. Telomere length maintenance plays an essential role in cell viability.
Multiple mechanisms in the regulation of ethanol‐inducible cytochrome P450IIE1
Authors: Koop Dennis R. , Tierney Daniel J.
Published: February 2005

Cytochrome P450IIE1 is involved in the metabolic activation of many xenobiotics involved with human toxicity. In particular, cellular concentrations of P450IIE1 are significantly induced by the most widely abused drug in our society today, alcohol. As a result, the synthesis and degradation of this form of P450 has significant health consequences. The regulation of the steady‐state concentration of P450IIE1 is an extremely complex process. The enzyme is regulated by transcriptional activation, mRNA stabilization, increased mRNA translatability and decreased protein degradation. The principal mechanism which controls the induction process depends on the chemical nature of the inducer, the age, and the nutritional and hormonal status of the animal. There also appear to be significant sex differences in the expression of P450IIE1. It is entirely possible that the regulation of the enzyme concentration under any given set of conditions will involve all of the mechanisms to different extents.
Mismatch repair in mammalian cells
Authors: Heywood Louise A. , Burke Julian F.
Published: February 2005

A vital process in maintaining a low genetic error rate is the removal of mismatched bases in DNA. The importance of this process in E. coli is demonstrated by the 100–1000 fold increase in mutation frequency observed in cells deficient in this repair system(1). Mismatches can arise as a consequence of recombination, errors in replication and as a result of spontaneous chemical deamination, the latter process resulting in an estimated twelve T:G mismatches per genome per day in mammalian cells(2). Recent studies, discussed here, provide evidence for the existence of specific mismatch repair systems in mammalian and human cells.
Defining components required for transport from the ER to the golgi complex in yeast
Authors: Newman Anna P. , Ferro‐Novick Susan
Published: February 2005

Several complementary approaches have been fruitful in the study of transport from the ER to the Golgi complex in yeast. Mutational analysis has led to the identification of genes required for this process, many of which are now being studied at the molecular and biochemical level. In the case of SEC18, DNA sequence analysis has demonstrated homology to a factor needed for transport in mammalian in vitro systems. In addition, the events that take place at this stage of the secretory pathway have been reconstituted in vitro.
Problems And Paradigms: Ionising radiations from nuclear establishments and childhood leukaemias – an enigma
Authors: Evans H. J.
Published: February 2005

The Gardner report, recently published in the UK, showing a correlation between incidence of childhood leukaemia and paternal exposure to ionising radiations (amongst fathers working in nuclear power plants) has added a new element to debates about both the risk factors in nuclear power plants and the relationships between ionising radiations and leukaemogenesis. The epidemiologic and genetic evidence concerning leukaemias is reviewed here and it is concluded that the leukaemogenic agent, whose existence is indicated in the Gardner report, is unlikely to be paternal radiation dose per se but rather exposure to another factor that is correlated with paternal radiation dose received.
Regional neural induction in Xenopus laevis
Authors: Sharpe Colin R.
Published: February 2005

During development of the Xenopus embryo, the formation of the nervous system depends on an inductive interaction between mesoderm and ectoderm. The result is a neural tube that is regionally differentiated along the anterior–posterior axis from forebrain to spinal cord (Fig. 1). The discovery of genes whose transcripts can be used as molecular markers for different regions of the nervous system has permitted reassessment of the existing theories of neural tissue formation. Although the neural inducing molecules remain elusive, the mechanism by which cells interact to form a regionally differentiated nervous system is becoming clearer.
Roots: Selective reminiscences of β‐lactam antibiotics: Early research on penicillin and cephalosporins
Authors: Abraham Edward
Published: February 2005

The discovery, made in Oxford, that crude penicillin could cure systemic and life‐threatening bacterial infections was followed by attempts to purify penicillin, to determine its structure and then to produce it by total chemical synthesis. The β‐lactam structure of the molecule, first proposed in October 1943, was a source of controversy until 1945. However, no useful chemical synthesis was achieved and fermentation became the commercial source of the antibiotic.

In 1953, one of the products of a Cephalosporium sp. from Sardinia was shown to be a new and hydrophilic penicillin (penicillin N). This was contaminated with a substance having the same side‐chain but a characteristic absorption spectrum. The latter, cephalosporin C, showed antibacterial activity but was not inactivated by a penicillinase. The determination of its β‐lactam structure and isolation of its nucleus enabled pharmaceutical companies to produce many semisynthetic cephalosporins.

A new tripeptide was later found to be an intermediate in the biosynthesis of both penicillin N and cephalosporin C, and this was followed by the complete elucidation of the biosynthetic pathways leading to these compounds and to benzylpenicillin.
Steroid hormone receptors and In vitro transcription
Authors: Allan George F. , Tsai Sophia Y. , O'Malley Bert W. , Tsai Ming‐Jer
Published: February 2005

Steroid hormone receptors are ligand‐inducible transcription factors that exhibit potent effects on gene expression in living cells. Precise dissection of their mode of action at the molecular level can best be carried out in functional cell‐free systems. This article will describe the benefits of such systems and review their development up to the recent establishment of steroid receptor‐dependent in vitro transcription. Subsequent advances in our knowledge of receptor function arising from the exploitation of this powerful experimental tool will be described. Particular emphasis will be placed upon two key problems: the role of steroid hormone in receptor action and the mechanisms by which steroid receptors activate gene transcription.
Structure and evolution of the actin crosslinking proteins
Authors: Dubreuil Ronald R.
Published: February 2005

The actin crosslinking proteins exhibit marked diversity in size and shape and crosslink actin filaments in different ways. Amino acid sequence analysis of many of these proteins has provided clues to the origin of their diversity. Spectrin, α‐actinin, ABP‐120, ABP‐280, fimbrin, and dystrophin share a homologous sequence segment that is implicated as the common actin binding domain. The remainder of each protein consists of repetitive and non‐repetitive sequence segments that have been shuffled and multiplied in evolution to produce a variety of proteins that are related in function and in composition, but that differ significantly in structure.
YACs and the C. elegans genome
Authors: Coulson Alan , Kozono Yoko , Lutterbach Bart , Shownkeen Ratna , Sulston John , Waterston Robert
Published: February 2005

During the past decade, it has become apparent that it is within our grasp to understand fully the development and functioning of complex organisms. It is widely accepted that this undertaking must include the elucidation of the genetic blueprint – the genome sequence – of a number of model organisms. As a prelude to the determination of these sequences, clonebased physical maps of the genomes of a number of multicellular animals and plants are being constructed. Yeast artificial chromosome (YAC) vectors, by virtue of their relatively unbiased cloning capabilities and capacity to carry large inserts, have come to play a central role in the construction of these maps. The application of YACs to the physical map of the Caenorhabditis elegans genome has enabled cosmid clone ‘islands’ to be linked together in an efficient manner. The long‐range continuity has improved the linkage between the genetic and physical maps, greatly increasing its utility. Since the genome can be represented by a relatively small number of YACs, it has been possible to make replica filters of genomically ordered YACs available to the community at large.
Inositol tetrakisphosphate as a second messenger: Confusions, contradictions, and a potential resolution
Authors: Irvine Robin F.
Published: February 2005

The second messenger function of inositol 1,4,5‐ trisphosphate (InsP3) is now well‐defined – it mobilizes Ca2+ from intracellular stores so that cytosolic Ca2+ increases. However, the function of inositol 1,3,4,5‐ tetrakisphosphate (InsP4) has proved much more difficult to fathom, as it has been reported to exert a wide variety of effects in a collection of experimental systems. In this review, a proposed molecular mechanism for InsP4 actions is discussed; it is suggested that InsP4 is the second messenger that controls Ca2+ entry into cells, and that it does so by binding to a receptor which itself interacts, directly or Indirectly, with the receptor for InsP3 It is proposed that this is InsP4's true physiological function, but the mechanism by which it exerts this function has led to confusing data concerning its action, and also to some misconceptions about how inositol phosphates control Ca2+ entry.
Alternative splicing of fibronectin: Three variants, three functions
Authors: Schwarzbauer Jean E.
Published: February 2005

Fibronectin (FN) is a multi‐functional extracellular matrix protein required for cell adhesion and migration, blood clotting, wound healing, and oncogenic transformation. The functional complexity is paralleled by structural diversity in that multiple forms of FN are generated by cell type‐specific alternative splicing. In the rat, up to 12 different combinations of the three alternatively spliced segments (EIIIA, EIIIB, and the V region) are produced. What effects do these segments have on FN function? Recently, progress has been made in the identification of specific activities for the three Variants of the V region, V120, V95, and V0. FN‐mediated cell adhesion, FN synthesis and secretion, and incorporation into blood clots are differentially affected by these isoforms. These results suggest that cellular behavior is modulated by environmental cues provided by different types and proportions of alternatively spliced FN variants.
Chromatin replication
Authors: Gruss Claudia , Sogo Josém.
Published: February 2005

Just as the faithful replication of DNA is an essential process for the cell, chromatin structures of active and inactive genes have to be copied accurately. Under certain circumstances, however, the activity pattern has to be changed in specific ways. Although analysis of specific aspects of these complex processes, by means of model systems, has led to their further elucidation, the mechanisms of chromatin replication in vivo are still controversial and far from being understood completely. Progress has been achieved in understanding: 1. The initiation of chromatin replication, indicating that a nucleosome‐free origin is necessary for the initiation of replication; 2. The segregation of the parental nucleosomes, where convincing data support the model of random distribution of the parental nucleosomes to the daughter strands; and 3. The assembly of histones on the newly synthesized strands, where growing evidence is emerging for a two‐step mechanism of nucleosome assembly, starting with the deposition of H3/H4 tetramers onto the DNA, followed by H2A/H2B dimers.
The function of melanin or six blind people examine an elephant
Authors: Hill Helene Z.
Published: February 2005

The pigment melanin is found in all living kingdoms and in many different structures and forms. When its various functions are examined separately, its behaviors seem disparate and conflicting. It has a clear role in camouflage and sexual display. Other major roles are examined critically. It can act as a sun screen but is not a very effective one. It can also scavenge active chemical species, but this, too, is not done very effectively. It produces active radicals that can damage DNA. It binds to drugs in ways that are either beneficial or deleterious. Aside from camouflage, its other roles can be brought together by a unifying hypothesis as first proposed by Proctor and McGinness nearly 20 years ago. Melanin is envisaged as an energy transducer with the properties of an amorphous semiconductor. It can absorb many different types of energy and dissipate them in the form of heat. However, if the energy input is too great, the output can be expressed in the form of activated chemical species that can damage cellular macromolecules resulting in cell death, mutations and cancer. The protective aspect of melanin in dark skin is seen as resulting from its high concentration and its confinement to ellipsoidal and densely packed organelles that can effectively shield the nucleus. In light skin, its radical nature is seen as potentially participating in the carcinogenic process, particularly when overwhelmed by intense episodes of sunburn.
Role of macrophages in peripheral nerve degeneration and repair
Authors: Perry V. H. , Brown M. C.
Published: February 2005

A cut or crush injury to a peripheral nerve results in the degeneration of that portion of the axon isolated from the cell body. The rapid degeneration of this distal segment was for many years believed to be a process intrinsic to the nerve. It was believed that Schwann cells both phagocytosed degenerating axons and myelin sheaths and also provided growth factors to promote regeneration of the damaged axons. In recent years, it has become apparent that the degenerating distal segment is invaded by monocytes from the blood. We will review the evidence that these recruited macrophages play a role in both degeneration and regeneration of peripheral nerve axons after injury and consider whether the slow degeneration and poor monocyte recruitment in the central nervous system may contribute to the poor regeneration there.
Retinoic acid and development of the central nervous system
Authors: Maden Malcolm , Holder Nigel
Published: February 2005

We consider the evidence that RA†, the vitamin A metabolite, is involved in three fundamental aspects of the development of the CNS: (1) the stimulation of axon outgrowth in particular neuronal sub‐types; (2) the migration of the neural crest; and (3) the specification of rostrocaudal position in the developing CNS (forebrain, midbrain, hindbrain, spinal cord). The evidence we discuss involves RA‐induction of neurites in cell cultures and explants of neural tissue; the teratological effects of RA on the embryo's nervous system; the observation that RA can be detected endogenously in the spinal cord; and the fact that the receptors and binding proteins for RA are expressed in precise domains and neuronal cell types within the nervous system.
The plant hormone auxin: Insight in sight
Authors: Estelle Mark
Published: February 2005

Physiological experiments conducted over the last 60 years indicate that the plant hormone auxin regulates a diverse set of developmental processes via changes in cell division, cell elongation and cell differentiation. Recent studies using transgenic plants with altered auxin levels support these conclusions and promise to provide more detailed information on the role of auxin during plant development. Although it is possible that all auxin responses are mediated by the same primary biochemical events, the studies described in this review are more consistent with multiple modes of auxin action. The development of molecular and genetic approaches to the study of hormone action should resolve this issue. The accelerated rate of progress in this field suggests that real insight into the mechanism of auxin action may be forthcoming.
Roots. Use of the HPRT gene and the HAT selection technique in DNA‐mediated transformation of mammalian cells: First steps toward developing hybridoma techniques and gene therapy
Authors: Szybalski Waclaw
Published: February 2005

In 1956, I decided to apply my experience in microbial genetics to developing analogous systems for human cell lines, including the selection of mutants with either a loss or gain of a biochemical function. For instance, mutants resistant to azahypoxanthine showed a loss of the HPRT enzyme (hypoxanthine phosphoribosyl transferase), whereas gain of the same enzyme was accomplished by blocking de novo purine biosynthesis with aminopterin, while supplying hypoxanthine and thymine (HAT selection). Using HAT selection, we: (i) genetically transformed HPRT− mutant cells to HPRT+ wild type by using DNA extracted from HPRT+ cells, and (ii) selected HPRT+ hybrid cells by fusing HPRT− D98/AH2 cells with skin cells. These approaches, which we dubbed in 1962 as a [first step toward gene therapy], contributed to the later development of (i) cell fusion techniques, (ii) the development of monoclonal antibodies, (iii) routine transformation of mammalian cells with cloned genes, and (iv) methods for creating transgenic organisms.
Myelin Po‐protein, more than just a structural protein?
Authors: Filbin Marie T. , Tennekoon Gihan I.
Published: February 2005

The protein Po has long been proposed to be responsible for the compact nature of peripheral myelin through interactions of both its extracellular and cytoplasmic domains. Recent studies support such a role for Po's extracellular region while more precise mapping of its adhesive domains are ongoing. As Po is a member of the immunoglobulin gene superfamily and perhaps bears the closest similarity to the ancestral molecule of this whole family, these studies may also have more general implications for adhesive interactions. In addition, although long believed to be purely an inert, structural molecule, Po has been reported to promote neurite outgrowth, which suggests a more dynamic role for this interesting molecule.
The biology of hepatocyte growth factor/scatter factor
Authors: Furlong Robert A.
Published: February 2005

Hepatocyte growth factor, a potent mitogen for epithelial and other cell types, and scatter factor, a stimulant of epithelial cell motility are identical. In addition to these mitogenic and motogenic functions, the factor has been shown to be an epithelial morphogen and also has antiproliferative effects in some cancer cell lines. The membrane receptor for hepatocyte growth factor/scatter factor has been identified as the c‐met proto‐oncogene product.
Problems and paradigns. Evolution of mitochondrial genomes and the genetic code
Authors: Kurland C. G.
Published: February 2005

Mitochondrial genomes are clearly marked by a strong tendency towards reductive evolution. This tendency has been facilitated by the transfer of most of the essential genes for mitochondrial propogation and function to the nuclear genome. The most extreme examples of genomic simplification are seen in animal mitochondria, where there also are the greatest tendencies to codon reassignment. The reassignment of codons to amino acids different from those designated in the so called universal code is seen in part as an expression of the reduction of the number of genes used by these genomes to code for tRNA species. The driving force for the reductive evolution of mitochondrial genomes is identifed with two population genetic effects which may also be operating on populations of parasites.
Mitochondrial DNA and genetic disease
Authors: Poulton Jo
Published: February 2005

Since the human mitochondrial genome was characterised and sequenced in 1981(1), it has been viewed as the likely site of genetic diseases showing a maternal inheritance pattern and associated with defects of the respiratory chain, such as the mitochondrial myopathies (MMs)†(2). The properties that make it a candidate for the source of such conditions are that it encodes polypeptides involved in electron transport(3,4) and that it is maternally inherited(5). However, several of the mtDNA diseases only fulfill one or other of these criteria: the first group of mtDNA diseases showed Only sporadic deletions(6,7), and the first point mutation in Leber's Hereditary Optic Neuropathy(8) (LHON) is not associated with a clear biochemical defect. Furthermore, it is now clear that both autosomal dominant(9) and probably recessive(10) nuclear genes can cause abnormalities of mtDNA. Each of these major groups will be considered in turn.
DNA triple‐helix formation: An approach to artificial gene repressors?
Authors: Maher L. James
Published: February 2005

Certain sequences of double‐helical DNA can be recognized and tightly bound by oligonucleotides. The effects of such triple‐helical structures on DNA binding proteins have been studied. Stabilities of DNA triple‐helices at or near physiological conditions are sufficient to inhibit DNA binding proteins directed to overlapping sites. Such proteins include restriction endonucleases, methylases, transcription factors, and RNA polymerases. These and Other results suggest that oligonucleotide‐directed triple‐helix formation could provide the basis for designing artificial gene repressors. The general question of whether biological systems employ RNA molecules for recognition and regulation of double‐helical DNA is discussed.
Sex‐chromosome pairing and activity during mammalian meiosis
Authors: Handel Mary Ann , Hunt Patricia A.
Published: February 2005

Mammalian sex chromosomes exhibit marked sexual dimorphism in behavior during gametogenesis. During oogenesis, the X chromosomes pair and participate in unrestricted recombination; both are transcriptionally active. However, during spermatogenesis the X and Y chromosomes experience spatial restriction of pairing and recombination, are transcriptionally inactive, and form a chromatin domain that is markedly different from that of the autosomes. Thus the male germ cell has to contend with the potential loss of X‐encoded gene products, and it appears that coping strategies have evolved. Genetic control of sex‐chromosome inactivation during spermatogenesis does not involve pairing or the presence of the Y chromosome or an intact X chromosome, and may therefore be under exogenous control by the gonad. Sex‐chromosome reactivation during oogenesis and inactivation during spermatogenesis probably reflect specific meiotic events such as recombination. Understanding these phenomena may help explain other sex‐related differences in genetic recombination.
Mouse albino‐deletions: From genetics to genes in development
Authors: Holdener‐Kenny Bernadette , Sharan Shyam K. , Magnuson Terry
Published: February 2005

Six essential genes located near the mouse albino locus have been identified as required during specific periods of development. Amongst these six, each is required either during the preimplantation stages of development, at specific times during gastrulation, within 12 hrs after birth or during juvenile development. These genes were identified as a result of extensive genetic complementation analysis using embryos homozygous for the albino deletions. Although, in principal, the associated developmental abnormalities could result from loss of multiple genes, the deletion phenotype in one case is identical to that induced by chemical mutagenesis. These results indicate that the abnormalities observed in deletion homozygotes may result from single gene loss. The deletions have proven useful not only as genetic tools to localize the position of the genes, but also as molecular entry points to the regions containing these genes. The current methodology being used to isolate candidate genes from the albino region is also reviewed here.
Bending of DNA by transcription factors
Authors: van der Vliet Peter C. , Verrijzer C. Peter
Published: February 2005

An increasing number of transcription factors both from prokaryotic and eukaryotic sources are found to bend the DNA upon binding to their recognition site. Bending can easily be detected by the anomalous electrophoretic behaviour of the DNA‐protein complex or by increased cyclization of DNA fragments containing the protein‐induced bend. Induction of DNA bending by transcription factors could regulate transcription in various ways. Bending may bring distantly bound transcription factors closer together by facilitating DNA‐looping or it could mediate the interaction between transcription factors and the general transcription machinery by formation of large nucleoprotein structures in which the DNA is wrapped around the protein complex. Alternatively, the energy stored in a protein‐induced bend could be used to favour formation of an open transcription complex or to dissociate the RNA polymerase in the transition from initiation to elongation. Modification of the bend angles and bending centers, caused by homodimerization or heterodimerization of transcription factors, may well turn out to be an important way to enlarge the range of interactions required for regulation of gene expression.
Interaction of rhodopsin with the G‐protein, transducin
Authors: Hargrave Paul A. , Hamm Heidi E. , Hofmann K. P.
Published: February 2005

Rhodopsin, upon activation by light, transduces the photon signal by activation of the G‐protein, transducin. The well‐studied rhodopsin/transducin system serves as a model for the understanding of signal transduction by the large class of G‐protein‐coupled receptors. The interactive form of rhodopsin, R*, is conformationally similar or identical to rhodopsin's photolysis intermediate Metarhodopsin II (MII). Formation of MII requires deprotonation of rhodopsin's protonated Schiff base which appears to facilitate some opening of the rhodopsin structure. This allows a change in conformation at rhodopsin's cytoplasmic surface that provides binding sites for transducin. Rhodopsin's 2nd, 3rd and putative 4th cytoplasmic loops bind transducin at sites including transducin's 5 kDa carboxyl‐terminal region. Site‐specific mutagenesis of rhodopsin is being used to distinguish sites on rhodopsin's surface that are important in binding transducin from those that function in activating transducin. These observations are consistent with and extend studies on the action of other G‐protein‐coupled receptors and their interactions with their respective G proteins.
Mechanism of action of the Escherichia coli UvrABC nuclease: Clues to the damage recognition problem
Authors: Van Houten Ben , Snowden Amanda
Published: February 2005

During the process of E. coli nucleotide excision repair, DNA damage recognition and processing are achieved by the action of the uvrA, uvrB, and uvrC gene products. The availability of highly purified proteins has lead to a detailed molecular description of E. coli nucleotide excision repair that serves as a model for similar processes in eukaryotes. An interesting aspect of this repair system is the protein complex's ability to work on a vast array of DNA lesions that differ widely in their chemical composition and molecular architecture. Here we propose a model for damage recognition in which the UvrB protein serves as the component that confers enhanced specificity to a preincision complex. We hypothesize that one major determinant for the formation of a stable preincision complex appears to be the disruption of base stacking interactions by DNA lesions.
Challenges: The pharmacological manipulation of members of the transforming growth factor beta family in the chemoprevention of breast cancer
Authors: Dickens Tracey‐Anne , Colletta Anthony A.
Published: February 2005

The transforming growth factors beta are a family of peptides which are involved in the regulation of cell growth and differentiation. It has been suggested that the loss of sensitivity to growth inhibition by endogenous TGF‐β may contribute to the process of carcinogenesis in epithelial systems. However, many breast cancer cells remain sensitive to the growth inhibitory effects of these peptides, suggesting that the local induction of TGF‐β could provide a pharmacological approach to chemoprevention. Triphenylethylene anti‐oestrogens, synthetic progestins and retinoids all offer potential as chemopreventative agents. A common feature of their mechanism of action is the ability to locally increase the production of the transforming growth factors beta.
What the papers say: Cellular dedifferentiation and spore germination in Dictyostelium may utilize similar regulatory pathways
Authors: Powell‐Coffman Jo Anne , Firtel Richard A.
Published: February 2005

Cellular dedifferentiation is an important developmental response to perturbations in morphogenesis. In the cellular slime mold Dictyostelium discoideum this process gives cells the flexibility, when multicellular development is disrupted, to respond to nutrients and reinitiate vegetative growth. Recent studies in D. discoideum described by Soll and colleagues(1) show that genes previously thought to be expressed only during spore germination are also expressed during induced dedifferentiation, suggesting that similar molecular mechanisms are involved in these two developmental processes. It should now be possible to determine whether the developmental programs that control dedifferentiation during spore germination also control conversion of cell types in the multicellular organism.
Protein trafficking along the exocytotic pathway
Authors: Hong Wanjin , Tang Bor Luen
Published: February 2005

Proteins of the exocytotic (secretory) pathway are initially targeted to the endoplasmic reticulum (ER) and then translocated across and/or inserted into the membrane of the ER. During their anterograde transport with the bulk of the membrane flow along the exocytotic pathway, some proteins are selectively retained in various intracellular compartments, while others are sorted to different branches of the pathway. The signals or structural motifs that are involved in these selective targeting processes are being revealed and investigations into the mechanistic nature of these processes are actively underway.
Anoxia, wound healing, VL30 elements, and the molecular basis of malignant conversion
Authors: Anderson Garth R. , Stoler Daniel L.
Published: February 2005

Although VL30 retrotransposable elements have been associated with certain cancers for nearly twenty years, because of their expression in rodent malignancies and recombination into murine sarcoma viruses, their causative role, if any, in cancer has been uncertain and enigmatic. Recent findings suggest loss of normal transcriptional control of specific VL30 element expression may make a critical contribution to tumor progression at a step associated with malignant conversion, by bringing into play a cellular program normally involved in wound healing. This program, the fibroblast anoxic response system, includes an adaptation to glycolytic metabolism, secretion of metalloproteinases, and activation of an endonuclease. While appropriate for facilitating debris removal during wound healing, loss of control of this program in a cell which has already progressed to the benign neoplastic state has the potential to simultaneously produce the invasiveness and genomic instability charateristic of malignancy. Examination of tumors and tumor derived cell lines has confirmed that key aspects of this system are in fact activated in cancer.
Hypothesis: An apparent dimerization motif in the third domain of alphafetoprotein: Molecular mimicry of the steroid/thyroid nuclear receptor superfamily
Authors: Mizejewski G. J.
Published: February 2005

Alpha‐fetoprotein (AFP)

AFP, alpha‐fetoprotein; T3R, thyroid hormone (triiodothyronine) receptor; RAR, retionic acid receptor; erbA, putative thyroid hormone receptor proto‐oncogene products; VDR, vitamin D receptor; MR, mineralocorticoid receptor; GR, glucocorticoid receptor; PR, progesterone receptor; AR, androgen receptor; HRE, hormone response element on DNA; RXR, retionic‐X‐receptor; RAP, receptor auxiliary (accessory) proteins; E, estrogen.

is a tumor‐associated fetal marker, associated both with tumor growth and with birth defects. AFP, whose precise function is unknown, has been classified as belonging to a protein superfamily together with albumin and vitamin D‐binding (Gc) protein. AFP has been shown to bind various ligands in vitro including fatty acids, estrogens, thyroid hormones and retinoic acids. The steroid/thyroid nuclear receptor superfamily of proteins has recently become a major focus of biomedical investigation regarding regulation of gene expression. These receptors are thought to bind to DNA‐hormone response elements (HRE) that affect growth, development, differentiation, reproduction and homeostasis. The HREs are known to share DNA sequences with the various members of the nuclear receptor superfamily. In the present report, the possibility of a leucine‐zipper dimerization (heptad) motif in the carboxy‐terminal third domain of both rodent and human AFP is postulated. The presence of nine such hydrophobic repeats in the third domain of the AFP molecule mimics the heptad dimerization repeats found in the retinoic acid, thyroid, e‐erbA and other members of the nuclear receptor superfamily. Computer analysis revealed that the most conservative matching occurred between AFP and the retinoic acid class of receptors. However, other superfamily members displayed 40–60% homology with 5 of 9 AFP heptads. These findings could provide a possible mechanism for explaining the growth‐regulatory properties (both inhibition and enhancement) that have been ascribed to AFP in the last decade.
Structure and function of the homeotic gene complex (HOM‐C) in the beetle, Tribolium castaneum
Authors: Beeman Richard W. , Stuart Jeffrey J. , Brown Susan J. , Denell Robin E.
Published: February 2005

The powerful combination of genetic, developmental and molecular approaches possible with the fruit fly, Drosophila melanogaster, has led to a profound understanding of the genetic control of early developmental events. However, Drosophila is a highly specialized long germ insect, and the mechanisms controlling its early development may not be typical of insects or Arthropods in general. The beetle, Tribolium castaneum, offers a similar opportunity to integrate high resolution genetic analysis with the developmental/molecular approaches currently used in other organisms. Early results document significant differences between insect orders in the functions of genes responsible for establishing developmental commitments.
The centromere of budding yeast
Authors: Hegemann Johannes H. , Fleig Ursula N.
Published: February 2005

Stable maintenance of genetic information during meiosis and mitosis is dependent on accurate chromosome transmission. The centromere is a key component of the segregational machinery that couples chromosomes with the spindle apparatus. Most of what is known about the structure and function of the centromeres has been derived from studies on yeast cells. In Saccharomyces cerevisiae, the centromere DNA requirements for mitotic centromere function have been defined and some of the proteins required for an active complex have been identified. Centromere DNA and the centromere proteins form a complex that has been studied extensively at the chromatin level. Finally, recent findings suggest that assembly and activation of the centromere are integrated in tethe cell cycle.
The crystal δ‐endotoxins of Bacillus thuringiensis: Models for their mechanism of action on the insect gut
Authors: Knowles Barbara H. , Dow Julian A. T.
Published: February 2005

The crystal δ‐endotoxins of Bacillus thuringiensis (Bt) are a family of insecticidal proteins which have been known for some time to kill insects by lysing their gut epithelial cells, but the precise molecular mechanism of toxicity has remained elusive. The recent publication of the crystal structure of a Bt δ‐endotoxin has made it possible for us to model the molecular events that occur as the toxin binds to its receptor and inserts into the membrane to form a pore. Using our knowledge of insect gut physiology, we can also predict the effect on the insect of the formation of a toxic pore. We present a new model to explain the events that occur in the insect gut during toxin action.
Intracellular pH regulation in the early embryo
Authors: Baltz Jay M.
Published: February 2005

Intracellular pH (pHi) regulation is a homeostatic function of all cells. Additionally, the plasma membrane‐based transporters controlling pHi are involved in growth factor activation, cell proliferation and salt transport – all processes active in early embryos. pHi regulation in the early embryos of many species exhibits unique features: in mouse preimplantation embryos, mechanisms for correcting excess acid apparently are inactive, while excess base is removed by the mechanism common in differentiated cells. Additionally, unlike differentiated cells, mouse preimplantation embryos are highly permeable to H+ until the blastocyst stage, where the epithelial cells surrounding the embryo are impermeable. In several non‐mammalian species, of which the best‐studied is sea urchin, cytoplasmic alkalinization at fertilization is necessary for development of the embryo, and elevated pHi must be maintained during early development. Thus, pHi regulatory mechanisms appear to be important for early embryo development in many species.
Localized RNAs and their functions
Authors: Ding Dali , Lipshitz Howard D.
Published: February 2005

The eukaryotic cell is partitioned by membranes into spatially and functionally discrete subcellular organelles. In addition, the cytoplasm itself is partitioned into discrete subregions that carry out specific functions. Such compartmentation can be achieved by localizing proteins and RNAs to different subcellular regions. This review will focus on localized RNAs, with a particular emphasis on RNA localization mechanisms and on the possible biological functions of localization of these RNAs. In recent years, an increasing number of localized RNAs have been identified in a variety of cell types among many animal species. Emphasis here will be on localized RNAs in the most intensively studied systems – Drosophila and Xenopus eggs and early embryos.
Molecular perspectives of chromosome pairing at meiosis
Authors: Moens Peter B.
Published: February 2005

Ideas about the mechanisms that regulate chromosome pairing, recombination, and segregation during meiosis have gained in molecular detail over the last few years. The purpose of this article is to survey briefly the shifts in paradigms and experiments that have generated new perspectives. It has never been very clear what it is that brings together the homologous chromosomes at meiotic prophase. For a while it appeared that the synaptonemal complex might be the nuclear organelle responsible for synapsis, but the supporting evidence has not been entirely convincing. Whatever the mechanism, it has always been assumed that homologous synapsis creates the opportunity for homologous DNA sequences to initiate recombination. At present, alternative ideas are developing. Attractive is the concept that double strand DNA repair mechanisms, that find and use the undamaged homologue for repair, have evolved into a meiotic mechanism for the recognition and pairing of homologous sequences. Subsequent intimate synapsis of homologous chromosomes in the context of the synaptonemal complex may serve later functions in the regulation of interference and segregation at first anaphase. A number of areas that are being tested at present and some that may be investigated in the future are discussed at the end of the review.
Ras regulatory interactions: Novel targets for anti‐cancer intervention?
Authors: Prendergast George C. , Gibbs Jackson B.
Published: February 2005

Advances in the understanding of Ras oncoprotein function suggest novel points for anti‐tumor intervention. First, upstream‐acting guanine nucleotide exchange factors and SH2/SH3 domain‐containing adaptor proteins that link Ras with growth factor receptor tyrosine kinases have recently been characterized. Second, work on downstream‐acting Ras effector functions including the Ras GTPase‐activating protein (p120GAP) and the Raf kinase has revealed direct biochemical interactions that are functionally required for oncogenic Ras signalling. We summarize progress in these areas and discuss the potential for novel applications to anti‐cancer chemotherapy.
The chaperonin cycle and protein folding
Authors: Lund Peter
Published: February 2005

The process of protein folding in the cell is now known to depend on the action of other proteins. These proteins include molecular chaperones, Which interact non‐covalently with proteins as they fold and improve the final yields of active protein in the cell. The precise mechanism by which molecular chaperones act is obscure. Experiments reported recently(1) show that for one molecular chaperone (Cpn60, typified by the E. coli protein GroEL), the folding reaction is driven by cycles of binding and release of the co‐chaperone Cpn10 (known as GroES in E. coli). These alternate with binding and release of the unfolded protein substrate. These cycles come about because of the opposite effects of Cpn10 and unfolded protein on the Cpn60 complex: the former stabilises the ADP‐bound state of Cpn60, whereas the latter stimulates ADP‐ATP exchange. This model proposes that the substrate protein goes through multiple cycles of binding and release, and is released into the cavity of the Cpn60 complex where it can undergo folding without interacting with other nearby folding intermediates. This is consistent with the ability of Cpn60 proteins to enhance folding by blocking pathways to aggregation.