bluuebunny/crossref_metadata_2025 huggingface dataset:
Membrane protein assembly: Rules of the game
Authors: von Heijne Gunnar
Published: February 2005

Integral membrane proteins are found in all cellular membranes and fulfil many of the functions that are central to life. A critical step in the biosynthesis of membrane proteins is their insertion into the lipid bilayer. The mechanisms of membrane protein insertion and folding are becoming increasingly better understood, and efficient methods for the ab initio prediction of three‐dimensional protein structure from the primary amino acid sequence may be within reach. Already, the basic tools needed for engineering and de novo design of integral membrane proteins seem to be at hand.
Regulation of protein traffic in polarized epithelial cells
Authors: Mostov Keith E. , Cardone Michael H.
Published: February 2005

The plasma membrane of polarized epithelial cells is divided into apical and basolateral surfaces, with different compositions. Proteins can be sent directly from the trans‐Golgi network (TGN) to either surface, or can be sent first to one surface and then transcytosed to the other. The glycosyl phosphatidylinositol anchor is a signal for apical targeting. Signals in the cytoplasmic domain containing a β‐turn determine basolateral targeting and retrieval, and are related to other sorting signals. Transcytosed proteins, such as the polymeric immunoglobulin receptor (plgR), are endocytosed from the basolateral surface and then accumulate in a tubular compartment concentrated underneath the apical surface. This compartment, tentatively termed the apical recycling compartment, may be a central sorting station, as it apparently receives material from both surfaces and sorts them for delivery to the correct surface. Delivery to the apical surface from both the TGN and the apical recycling compartment appears to be regulated by protein kinases A and C, and endocytosis from the apical surface is also regulated by kinases. Transcytosis of the plgR is additionally regulated by phosphorylation of the plgR and by ligand binding to the plgR. Regulation of traffic in polarized epithelial cells plays a central role in cellular homeostasis, response to external signals and differentiation.
Signal transduction through integrins: A central role for focal adhesion kinase?
Authors: Richardson Alan , Parsons J. Thomas
Published: February 2005

The integrins are receptors for proteins of the extracellular matrix, both providing a physical link to the cytoskeleton and transducing signals from the extracellular matrix. Activation of integrins leads to tyrosine and serine phosphorylation of a number of proteins, elevation of cytosolic calcium levels, cytoplasmic alkalinization, changes in phospholipid metabolism and, ultimately, changes in gene expression. The recently discovered focal adhesion kinase localizes to focal contacts, which are sites of integrin clustering, and focal adhesion kinase can physically associate with integrins in vitro. As integrins lack intrinsic catalytic activity, focal adhesion kinase is a candidate for a signaling molecule that is recruited by integrins in order to trigger the generation of intracellular second messengers. Thus, focal adhesion kinase may play a central role in signal transduction through integrins.
Ductin – a proton pump component, a gap junction channel and a neurotransmitter release channel
Authors: Finbow Malcolm E. , Harrison Michael , Jones Phillip
Published: February 2005

Ductin is the highest conserved membrane protein yet found in eukaryotes. It is multifunctional, being the subunit c or proteolipid component of the vacuolar H+‐ATPase and at the same time the protein component of a form of gap junction in metazoan animals. Analysis of its structure shows it to be a tandem repeat of two 8‐kDa domains derived from the subunit c of the F0 proton pore from the F1F0 ATPase. Each domain contains two transmembrane α‐helices, which together may form a four‐helix bundle. In both the V‐ATPase and gap junction channel, ductin is probably arranged as a hexamer of subunits forming a central channel of gap junction‐like proportions. The two functions appear to be seggregated by ductin having two orientations in the bilayer. Ductin is also the major component of the mediatophore, a protein complex which may aid in the release of neurotransmitters across the pre‐synaptic membrane. It is also a target for a class of poorly understood viral polypeptides. These polypeptides are small and highly hydrophobic and some have oncogenic activity. Ductin thus appears to be at the crossroads of a number of biological processes.
c‐Fos and bone loss: A proto‐oncogene regulates osteoclast lineage determination
Authors: Jacenko Olena
Published: February 2005

Development of gene transfer systems provides a key tool for understanding gene function. Exciting and often unexpected consequences from embryo manipulations are yielding insights into molecular mechanisms underlying development under normal and pathogenic states, and are providing animal models for diseases. Contributing to this progress is the elegant work on c‐fos(1), where Wagner and coworkers identify this proto‐oncogene as a primary factor which directs cell differentiation along the osteoclast/macrophage lineages, and thus regulates bone remodeling. Their studies support a link between skeletogenesis, marrow formation and hematopoiesis, and may help to delineate mechanisms underlying the oncogenic transformation of skeletal and hematopoietic cells.
Ethylene: A tiny molecule with great potential
Authors: Woltering Ernst J. , de Vrije Truus
Published: February 2005

Ethylene (C2H4) is a gaseous plant hormone produced by higher and lower (green) plants and, when grown on appropriate substrates, also by fungi, yeasts and bacteria. Ethylene is involved in many developmental processes in plants and is biologically active in trace amounts (10 – 100 nl/I of air) that may be present in the outside air due to industrial air pollution(1). Fruit ripening and flower senescence especially, in a variety of commercially important crops, are dramatically stimulated by ethylene. Following characterization of the genes coding for the key enzymes in ethylene biosynthesis, i.e. ACC synthase and ACC oxidase, it has become clear that their expression is regulated in a complex manner involving developmental, hormonal and tissue‐specific factors. This was recently very elegantly demonstrated for the expression of ACC oxidase genes in developing petunia flowers by Tang et al.(2). The spatial and temporal expression patterns, especially in the reproductive organs, suggest a hitherto unknown role for ethylene in reproductive processes such as the self‐incompatible response and the secretion of cellular exudate by the stigma and nectary.
Structure‐function relationships in Src family and related protein tyrosine kinases
Authors: Superti‐Furga Giulio , Courtneidge Sara A.
Published: February 2005

There is increasing evidence to suggest that cytoplasmic tyrosine kinases of the Src family have a pivotal role in the regulation of a number of cellular processes. Members of this family have been implicated in cellular responses to a variety of extracellular signals, such as those arising from growth factors and cell‐cell interactions, as well as in differentiative and developmental processes in both vertebrates and invertebrates. A better understanding of the regulation and of the structure‐function relationships of these enzymes might aid in the development of specific ways to interfere with their action, as well as serving as a paradigm for regulation of other protein tyrosine kinases that have SH2 and SH3 domains. In this review we will first discuss the regulation of Src family protein tyrosine kinases, with particular emphasis on their SH2 and SH3 domains. We will then briefly review other non‐receptor protein tyrosine kinases that have SH2 and SH3 domains.
Ciliogenesis in sea urchin embryos – a subroutine in the program of development
Authors: Stephens R. E.
Published: February 2005

One major milestone in the development of the sea urchin embryo is the assembly of a single cilium on each blastomere just before hatching. These cilia are constructed both from pre‐existing protein building blocks, such as tubulin and dynein, and from a number of 9+2 architectural elements that are synthesized de novo at ciliogenesis. The finite or quantal synthesis of certain key architectural proteins is coincident with ciliary elongation and proportional to ciliary length. Upon deciliation, the synthesis of architectural proteins occurs anew, a new cilium grows, and the stores of various building blocks are replenished. This routine of coordinated ciliary gene expression may be replayed experimentally many times without delaying normal development. The ability to regenerate cilia has allowed elucidation of these various protein synthetic relationships and has led to the discovery of the pathways by which membrane‐associated tubulin and axoneme‐associated architectural proteins are conveyed into the highly compartmentalized growing cilium. The sea urchin embryo thus provides a very convenient model system for studies of ciliary assembly and maintenance, coordinate gene expression and membrane dynamics.
MYB: An old oncoprotein with new roles
Authors: Thompson M. Anne , Ramsay Robert G.
Published: February 2005

Over the last decade, the c‐myb gene and its protein product, Myb, have undergone extensive examination and manipulation in hemopoietic tissues. Although it is rarely disputed that, as a transcription factor, Myb regulates cell cycling, proliferation and differentiation, identification of genes directly controlled by Myb has been surprisingly difficult. More recently, genes with promoter regions that contain Myb recognition sequences have been identified, but a direct proliferative response to Myb via these ‘target genes’ has yet to be demonstrated. Mutagenesis studies have defined domains of the protein which influence its transcriptional activity and transforming potential; however how the molecule interacts with itself and with other cellular factors is only beginning to be understood. A broader examination of c‐myb expression in normal and malignant tissues suggests an analogous role for Myb in proliferation, differentiation and transformation of nonhemopoietic tissues.
Guanine nucleotide exchange factors: Activators of the Ras superfamily of proteins
Authors: Quilliam Lawrence A. , Khosravi‐Far Roya , Huff Shayne Y. , Der Channing J.
Published: February 2005

Ras proteins function as critical relay switches that regulate diverse signaling pathways between cell surface receptors and the nucleus. Over the past 2‐3 years researchers have identified many components of these pathways that mediate Ras activation and effector function. Among these proteins are several guanine nucleotide exchange factors (GEFs), which are responsible for directly interacting with and activating Ras in response to extracellular stimuli. Analogous GEFs regulate Ras‐related proteins that serve other diverse cellular functions. In particular, a growing family of proteins (Dbl homology proteins) has recently been identified, which may function as GEFs for the Rho family of Ras‐related proteins. This review summarizes our current knowledge of the structure, biochemistry and biology of Ras and Rho family GEFs. Additionally, we describe mechanisms of GEF activation of Ras in signal transduction and address the potential that deregulated GEFs might contribute to malignant transformation through chronic Ras protein activation.
Cyclin‐dependent protein kinases: Key regulators of the eukaryotic cell cycle
Authors: Nigg Erich A.
Published: February 2005

Passage through the cell cycle requires the successive activation of different cyclin‐dependent protein kinases (CDKs). These enzymes are controlled by transient associations with cyclin regulatory subunits, binding of inhibitory polypeptides and reversible phosphorylation reactions. To promote progression towards DNA replication, CDK/cyclin complexes phosphorylate proteins required for the activation of genes involved in DNA synthesis, as well as components of the DNA replication machinery. Subsequently, a different set of CDK/cyclin complexes triggers the phosphorylation of numerous proteins to promote the profound structural reorganizations that accompany the entry of cells into mitosis. At present, much research is focused on elucidating the links between CDK/cyclin complexes and signal transduction pathways controlling cell growth, differentiation and death. In future, a better understanding of the cell cycle machinery and its deregulation during oncogenesis may provide novel opportunities for the diagnostic and therapeutic management of cancer and other proliferation‐related diseases.
G1 regulation and checkpoints operating around START in fission yeast
Authors: Woollard Alison , Nurse Paul
Published: February 2005

Three major aspects of G1 regulation acting at START in fission yeast are discussed in this review. Firstly, progression towards S phase in the mitotic cycle. This is controlled by the activation of transcription complexes at START which cause cell cycle‐dependent activation of genes required for DNA synthesis. The second aspect is the regulation of developmental fate occurring during G1. Passage through START appears to inhibit sexual differentiation because the meiotic and mitotic pathways are mutually exclusive. This is brought about because the meiotic pathway is inhibited by the same gene functions that are required for S phase onset. Thirdly, distinct checkpoint, or dependency, controls operate both pre‐ and post‐START in the mitotic cycle to inhibit mitosis in the absence of replicated DNA, and also to limit rounds of DNA replication to one per cell cycle.
Human Papillomavirus E6 and E7: Proteins which deregulate the cell cycle
Authors: Tommasino Massimo , Crawford Lionel
Published: February 2005

Numerous clinical, epidemiological and molecular findings link some types of Human Papillomaviruses (HPV) with cancer of the genital tract. They share a common pathway of transformation with a number of DNA tumour viruses, such as Adenovirus and SV40. Although all these viruses are termed ‘DNA tumour viruses’ and have similar in vitro transforming activities, Human Papillomavirus is the only one so far clearly involved in human cancer. Extensive studies on HPV E6 and E7 proteins have demonstrated their involvement in malignant transformation. E6 and E7 bind the products of tumour suppressor genes, p53 and Rb1, respectively, modifying or inactivating their normal functions. The Rb1 and p53 genes are deleted or mutated in several cancers and both proteins regulate the transcription of genes involved in cell cycle progression control. The E6/p53 and E7/Rb1 interactions result in a deregulation of the cell cycle with loss of control of crucial cellular events, such as DNA replication, DNA repair and apoptosis.
Cell shape and chromosome partition in prokaryotes or, why E. coli is rod‐shaped and haploid
Authors: Donachie William D. , Addinall Stephen , Begg Ken
Published: February 2005

In the rod‐shaped cells of E. coli, chromosome segregation takes place immediately after replication has been completed. A septum then forms between the two sister chromosomes. In the absence of certain membrane proteins, cells grow instead as large, multichromosomal spheres that divide successively in planes that are at right angles to one another. Although multichromosomal, the spherical cells cannot be maintained as heterozygotes. These observations imply that, in these mutants, each individual chromosome gives rise to a separate clone of descendant cells. This suggests a model in which sites for cell division form between pairs of sister chromosomes at the time of segregation, but are not used in spherical cells until further rounds of replication have taken place, thus ensuring clonal (‘hierarchical’) segregation of chromosomes into progeny cells. The role of the morphogenetic membrane proteins is to convert the basically spherical cell into a cylinder that is able to divide as soon as replication and segregation have been completed, and thus to maximise the number of viable cells per genome.
Fractious chromosomes: Hybrid disruption and the origin of selfish genetic elements
Authors: McVean Gilean T.
Published: February 2005

Supernumerary B chromosomes are dispensable elements of the genome which can be retained in populations at high frequencies, despite being deleterious, through the ability to undergo non‐Mendelian inheritance. Their mode of origin is, however, obscure. Recent work on gynogenetic fish has demonstrated the incorporation of small, unstable, centromere‐containing microchromosomes, probably of interspecific derivation, into an asexual lineage(1). That these resemble B chromosomes both in structure and behaviour is consistent with the proposal that hybridisation between closely related species may be a significant mode of origin for such selfish genetic elements. Additional work on the B chromosome of a parasitoid wasp and observations on patterns of chromosome breakage from somatic cell hybrids also support this hypothesis.
Are competing intermolecular and intramolecular interactions of PERIOD protein important for the regulation of circadian rhythms in Drosophila?
Authors: Price Jeffrey L.
Published: February 2005

Genetic analysis is revealing molecular components of circadian rhythms. The gene products of the period gene in Drosophila and the frequency gene in Neurospora oscillate with a circadian rhythm. A recent paper(1) has shown that the PERIOD protein can undergo both intermolecular and intramolecular interactions in vitro. The effects of temperature and two period mutations on these molecular interactions were compared to the effects of the mutations and temperature on the in vivo period length of circadian rhythms. The results suggest that the molecular interactions may compete to maintain a rhythm with a constant period over a wide temperature range.
bcl‐2, a novel reguator of cell death
Authors: Hockenbery David M.
Published: February 2005

The bcl‐2 gene product, a 25 kDa membrane protein residing at mitochondrial, microsomal and nuclear membrane sites within many cell types, is a broad and potent inhibitor of cell death by apoptosis. A family of bcl‐2‐related genes with death‐inhibiting or ‐promoting activities has recently been described, indicating a potentially quite complex cell death regulatory network at the level of gene expression and protein‐protein interactions. The function of bcl‐2 may be to regulate a final common pathway in apoptosis. Current hypotheses suggest that oxidative stress, specific proteolytic activity or cell cycle control may be common elements in apoptosis through which bcl‐2 exerts its survival function. Based on the extent to which elements of apoptotic pathways overlap with non‐apoptotic cellular functions, the physiological role of bcl‐2 may also extend to other cellular processes such as differentiation and proliferation.
Drosophila WARTS–tumor suppressor and member of the myotonic dystrophy protein kinase family
Authors: Watson Kellie L.
Published: February 2005

Tumor suppressor genes represent a broad class of genes that normally function in the negative regulation of cell proliferation. Loss‐of‐function mutations in these genes lead to unrestrained cell proliferation and tumor formation. A fundamental understanding of how tumor suppressor genes regulate cell proliferation and differentiation should reveal important aspects of signalling pathways and cell cycle control. A recent report describing the Drosophila tumor suppressor gene warts has implications in the study of the human myotonic dystrophy gene(1). These genes encode members of a cyclic AMP‐dependent protein kinase subfamily that includes other plant and animal orthologues.
Animal models of polycystic kidney disease
Authors: Aziz Nazneen
Published: February 2005

Polycystic kidney disease (PKD) is one of the most prevalent causes of heritable renal failure. The disease is characterized by the occurrence of numerous fluid‐filled cysts within the parenchyma of kidney. The cysts are epithelial in origin and expand in size, leading to crowding of normal kidney tissue. Ultimately, there is gross enlargement of the kidneys with loss of normal functions, and death usually occurs because of complications related to renal failure. Animal models of polycystic kidney disease are proving to be extremely useful for studying the molecular basis of renal cyst formation and for the isolation of genes carrying the mutations. This article describes the various animal models of polycystic kidney disease, spontaneously and experimentally derived, that have recently been identified.
Axes, boundaries and coordinates: The ABCs of fly leg development
Authors: Held Lewis I.
Published: February 2005

Recent studies of gene expression in the developing fruitfly leg support a model – Meinhardt's Boundary Model – which seems to contradict the prevailing paradigm for pattern formation in the imaginal discs of Drosophila – the Polar Coordinate Model. Reasoning from geometric first principles, this article examines the strengths and weaknesses of these hypotheses, plus some baffling phenomena that neither model can comfortably explain. The deeper question at issue is: how does the fly's genome encode the three‐dimensional anatomy of the adult? Does it demarcate territories and boundaries (as in a geopolitical map) and then use those boundaries and their points of intersection as a scaffolding on which to erect the anatomy (the Boundary Model)? Or does it assign cellular fates within a relatively seamless coordinate system (the Polar Coordinate Model)? The existence of hybrid Cartesian‐polar models shows that the alternatives may not be so clear‐cut: a single organ might utilize different systems that are spatially superimposed or temporally sequential.
Reelin: A novel extracellular matrix protein involved in brain lamination
Authors: Rugarli Elena I. , Ballabio Andrea
Published: February 2005

Normal development of the nervous system is achieved through an elaborate program of guided neuronal migration and axonal growth. In the last few years, a flood of research has dissected the molecular bases of these phenomena, and several cell‐surface and extracellular matrix molecules, which are implicated in neuronal and axonal targeting processes, have been recognized. Taking this knowledge a step further, a recent paper by Tom Curran's group(1) reports the molecular cloning of the gene deleted in the autosomal recessive mouse mutation reeler, affecting cortical neuronal migration. This gene encodes reelin, a novel extracellular matrix protein.
Towards unravelling the Igf2/H19 imprinted domain
Authors: Viville Stéphane , Surani M. Azim
Published: February 2005

Genomic imprinting is an epigenetic marking process that confers parent‐of‐origin‐dependent expression on certain genes. These imprinted genes are sometimes found in clusters, suggesting a possible involvement of higher order regulatory elements controlling expression and imprinting of genes organised in such clusters. In the distal chromosome 7 there are at least four imprinted genes: Mash2, Ins2, Igf2 and H19. Recent evidence(1) suggests that imprinting and expression of at least Igf2 and H19 may be mechanistically linked.
Cytomegalovirus and atherosclerosis
Authors: Melnick Joseph L. , Adam Ervin , Debakey Michael E.
Published: February 2005

Finding that an avian herpesvirus can cause atherosclerosis in chickens prompted studies of human herpesviruses in human atherosclerosis. Antigens and nucleic acid sequences of cytomegalovirus (CMV), a widespread member of the herpesvirus family, were found in arterial lesions in human atherosclerosis, but infectious virus has not been observed. In atherosclerosis patients, high levels of CMV antibodies are present, suggesting the presence of virus that had been activated from a latent state. Atherosclerosis also develops in immunesuppressed heart transplant patients infected with CMV. The properties of CMV are consistent with its involvement at several levels of the atherogenic process. If this concept is correct, immunization with a CMV vaccine should prevent CMV infection and atherosclerosis.
Protein synthesis in eukaryotic organisms: New insights into the function of translation initiation factor EIF‐3
Authors: Hannig Ernest M.
Published: February 2005

The pathway for initiation of protein synthesis in eukaryotic cells has been defined and refined over the last 25 years using purified components and in vitro reconstituted systems. More recently, powerful genetic analysis in yeast has proved useful in unraveling aspects of translation inherently more difficult to address by strictly biochemical approaches. One area in particular is the functional analysis of multi‐subunit protein factors, termed eukaryotic initiation factors (eIFs), that play an essential role in translation initiation. eIF‐3, the most structurally complex of the eIFs, has until recently eluded this approach. The identification of the yeast GCD10 gene as the structural gene for the ζ subunit of yeast eIF‐3(1) and the analysis of mutant phenotypes has opened the door to the genetic dissection of the eIF‐3 protein complex.
Menage á trois: Double strand break repair, V(D)J recombination and DNA‐PK
Authors: Jeggo Penny A. , Taccioli Guillermo E. , Jackson Stephen P.
Published: February 2005

All organisms possess mechanisms to repair double strand breaks (dsbs) generated in their DNA by damaging agents. Site‐specific dsbs are also introduced during V(D)J recombination. Four complementation groups of radiosensitive rodent mutants are defective in the repair of dsbs, and are unable to carry out V(D)J recombination effectively. The immune defect in Severe Combined Immunodeficient (scid) mice also results from an inability to undergo effective V(D)J recombination, and scid cell lines display a repair defect and belong to one of these complementation groups. These findings indicate a mechanistic overlap between the processes of DNA repair and V(D)J recombination. Recently, two of the genes defined by these complementation groups have been identified and shown to encode components of DNA‐dependent protein kinase (DNA‐PK). We review here the three fields which have become linked by these findings, and discuss the involvement of DNA‐PK in dsb rejoining and in V(D)J recombination.
Towards unraveling the complexity of T cell signal transduction
Authors: Zenner Georg , zur Hausen Jan Dirk , Burn Paul , Mustelin Tomas
Published: February 2005

Activation of resting T lymphocytes through the T cell antigen receptor complex is initiated by critical phosphorylation and dephosphorylation events that regulate the function and interaction of a number of signaling molecules. Key elements in these reactions are members of the Src, Syk and Csk families of protein tyrosine kinases (PTKs) and the phosphotyrosine phosphatases (PTPases) that regulate and/or counteract them, such as CD45. The PTKs can autophosphorylate and phosphorylate each other at multiple sites and, as the result of these interactions, they are induced to phosphorylate other cellular proteins. These phosphorylation events lead to modulation of enzymatic activities and/or serve as binding sites for other signaling molecules having phosphotyrosine‐binding Src homology 2 (SH2) domains. As a result, these proteins translocate to the receptor complexes and are juxtaposed to the kinases that phosphorylate them. Some of the SH2‐domain‐containing polypeptides lack enzymatic activities and, instead, serve as adapter molecules that couple the signal to downstream effectors, such as regulators of the Ras proteins, and further into serine/threonine‐specific protein kinase cascades. Through largely unknown steps these reactions lead to the transcription of previously silent genes, activation of lymphocyte effector functions, progression through the cell cycle and cell proliferation.
Endless quest
Authors: Holliday Robin
Published: February 2005

The replication of linear chromosome DNA by DNA polymerase leads to the loss of terminal sequences, in the absence of a special mechanism to maintain ends or telomeres. This mechanism is known to consist of short terminal repeats and the enzyme telomerase, which contains RNA complementary to the DNA repeats. There is evidence that telomeric DNA continually decreases in size in the absence of telomerase, and this is followed by cellular senescence. Immortalisation of somatic cells is accompanied, at least in some cases, by acquisition of telomerase activity. The cloning of DNA coding for the RNA component of telomerase has opened up some new experimental approaches, including the study of telomerases with mutant RNA(1,2). The telomere theory of cellular senescence appears to provide a molecular basis for the ‘Hayflick limit’ to human fibroblast growth. However the telomeres and behaviour of primary mouse cells are anomolous(3), and many immortalised human cell lines lack normal telomerase activity(4). These exceptions are not easily accommodated in the telomere theory.
Membrane adhesion and other functions for the myelin basic proteins
Authors: Staugaitis Susan M. , Colman David R. , Pedraza Liliana
Published: February 2005

The myelin basic proteins are a set of peripheral membrane polypeptides which play an essential role in myelination. Their most well‐documented property is the unique ability to ‘seal’ the cytoplasmic aspects of the myelin membrane, but this is probably not the only function for these highly charged molecules. Despite extensive homology, the individual myelin basic proteins (MBPs) exhibit different expression patterns and biochemical properties, and so it is now believed that the various isoforms are not functionally equivalent in myelinating cells. We now think that while the major MBPs are intracellular adhesion molecules, some of the quantitatively less abundant isoforms that are expressed very early in development may have regulatory effects on the myelination program.
Early studies on human chromosomes
Authors: Harnden D. G.
Published: February 2005

The author describes his introduction to the field of cytogenetics, with his first viewing of himself, cytogenetically, down the microscope, and the progression of human cytogenetics as an area of study up to its modern integration with molecular genetics and computer technology.
Dorsoventral axis inversion: A phylogenetic perspective
Authors: Lacalli Thurston
Published: February 2005

Recent molecular evidence suggests that the body plans of insects and vertebrates may be dorsoventrally inverted with respect to one another. This poses a major challenge for comparative zoologists, either to explain how this came about or to offer alternative interpretations of the data. Dorsoventral inversion is most easily explained if the mouth of deuterostome metazoans (which would include vertebrates) is truly a secondary structure unrelated to the protostome mouth, located opposite to the latter on the dorsal surface of the body. Two possibilities are (1) that the definitive deuterostome mouth has replaced a preexisting protostome‐type mouth, or (2) that ancestral deuterostomes lacked a protostome‐type mouth altogether, and formed a secondary dorsal mouth entirely de novo. Our current understanding of invertebrate embryogenesis and larval morphology provides at least as much support, if not more, for (2) as for (1). By implication, even if ancestral protostomes and deuterostomes shared common anteroposterior and dorsoventral patterning systems, they may still have differed significantly with respect to other aspects of body organization and been otherwise very dissimilar organisms.
Chromosome healing: Spontaneous and programmed de novo telomere formation by telomerase
Authors: Melek Meni , Shippen Dorothy E.
Published: February 2005

Telomeres are protective caps for chromosome ends that are essential for genome stability. Broken chromosomes missing a telomere will not be maintained unless the chromosome is ‘healed’ with the formation of a new telomere. Chromosome healing can be a programmed event following developmentally regulated chromosome fragmentation, or it may occur spontaneously when a chromosome is accidentally broken. In this article we discuss the consequences of telomere loss and the possible mechanisms that the enzyme telomerase employs to form telomeres de novo on broken chromosome ends.
Is the Y chromosome of Drosophila an evolved supernumerary chromosome?
Authors: Hackstein Johannes H. P. , Hochstenbach Ron , Hauschteck‐Jungen Elisabeth , Beukeboom Leo W.
Published: February 2005

The Y chromosomes of most Drosophila species are necessary for male fertility but they are not involved in sex determination. They have many puzzling properties that resemble the effects caused by B chromosomes. Classical genetic and molecular studies reveal substantial affinities between Y and B chromosomes and suggest that the Y chromosomes of Drosophila are not degenerated homologues of the X chromosomes, but rather that their Y chromosomes evolved as specialized supernumeraries similar to classical B chromosomes.
Cooperative relaxation of supercoils and periodic transcriptional initiation within polymerase batteries
Authors: Guptasarma Purnananda
Published: February 2005

Transcription and DNA supercoiling are known to be linked by a cause‐effect relationship that operates in both directions. It is proposed here that this two‐way relationship may be exploited by the E. coli genome to facilitate constitutive transcription of supercoil‐sensitive genes by polymerase batteries made up of uniformly spaced RNA polymerase elongation complexes. Specifically, it is argued that (1) polymerases transcribing DNA in tandem cooperate to relax each other's transcription‐driven positive supercoils; and (2) negative supercoils driven upstream by elongation complexes tend to be ‘harnessed’ and used to cooperatively (and periodically) initiate fresh transcription from promoters. Harnessing of transcription‐driven negative supercoils is thought to be achieved through the erection of protein barriers to the rotational upstream propagation of supercoils from transcription events. The possible relevance of such cooperation amongst polymerases to the activation of transcription by DNA‐binding protein factors is emphasized. Some testable predictions are made and implications are discussed.
New strategies for treating AIDS
Authors: Sandstrom Paul A. , Folks Thomas M.
Published: February 2005

To date, the effective management of HIV‐1 infection by anti‐retroviral drugs has proved remarkably difficult to achieve. This is primarily due to the ease with which HIV‐1 becomes resistant to drugs which initially may be very effective at blocking viral replication. In a recent issue of Science, two promising new AIDS treatments were reported. The first described the use of retroviral‐type zinc finger structures found in the HIV‐1 nucleocapsid protein as targets for anti‐retroviral drugs(1). The second demonstrated the feasibility of the reverse transcriptase inhibitor (R)‐9‐(2‐phosphonylmethoxypropyl) adenine as a postexposure prophylaxis in blocking HIV‐1 infection(2).
Do imprinted genes have few and small introns?
Authors: Haig David
Published: February 2005

A gene is described as imprinted if its pattern of expression depends on whether it passed the previous generation in a male or female germ line. A recent paper(1) reports that imprinted genes have fewer and smaller introns than a control set of genes. The differences are striking but their interpretation is unclear. The loss of introns after a gene becomes imprinted is not sufficient to explain why imprinted genes have fewer introns than average, because related unimprinted genes also have few introns. Similarly, small introns appear to be a property of chromosomal region rather than of imprinting status itself, because neighboring unimprinted genes also have small introns.
Intracellular trafficking of lysosomal membrane proteins
Authors: Hunziker Walter , Geuze Hans J.
Published: February 2005

Lysosomes are the site of degradation of obsolete intracellular material during autophagy and of extracellular macromolecules following endocytosis and phagocytosis. The membrane of lysosomes and late endosomes is enriched in highly glycosylated transmembrane proteins of largely unknown function. Significant progress has been made in recent years towards elucidating the pathways by which these lysosomal membrane proteins are delivered to late endosomes and lysosomes. While some lysosomal membrane proteins follow the constitutive secretory pathway and reach lysosomes indirectly via the cell surface and endocytosis, others exit the trans‐Golgi network in clathrin‐coated vesicles for direct delivery to endosomes and lysosomes. Sorting from the Golgi or the plasma membrane into the endosomal system is mediated by signals encoded by the short cytosolic domain of these proteins. This review will discuss the role of lysosomal membrane proteins in the biogenesis of the late endosomal and lysosomal membranes, with particular emphasis on the structural features and molecular mechanisms underlying the intracellular trafficking of these proteins.
Dosage‐dependent modification of position‐effect variegation in Drosophla
Authors: Henikoff Steven
Published: February 2005

Many loci in Drosophila exhibit dosage effects on single phenotypes. In the case of modifiers of position‐effect variegation, increases and decreases in dosage can have opposite effects on variegating phenotypes. This is seemingly paradoxical: if each locus encodes a limiting gene product sensitive to dosage decreases, then increasing the dosage of any one should have no effect, because the others should remain limiting. An earlier model put forward to resolve this paradox suggested that dosage‐dependent modifiers encode protein subunits of a macromolecular complex that is sensitive to mass action equilibrium conditions. Because chemical equilibria are dynamic, however, such hypothetical complexes will be unstable to an extent that is inconsistent with the known properties of molecules that make up chromatin. An alternative model accounts for the dosage effects in terms of interactions between structural proteins that bind at multiple linked sites. These might include indirect interactions occurring between regulatory proteins and genes for structural proteins or their protein products. The large number of direct and inverse regulatory genes which are known to exist in Drosophila could account for the apparent genetic complexity that is seen for modifiers of position‐effect variegation and for other systems of phenotypic modification.
Dynamic property of intermediate filaments: Regulation by phosphorylation
Authors: Inagaki Masaki , Matsuoka Yoichiro , Tsujimura Kunio , Ando Shoji , Tokui Toshiya , Takahashi Toshitada , Inagaki Naoyuki
Published: February 2005

Site‐specific phosphorylation of intermediate filament (IF) proteins on serine and threonine residues leads to alteration of the filament structure, in vitro and in vivo. Protein kinases involved in cell signaling and those activated in mitosis dynamically control spatial and temporal organization of intracellular IF phosphorylation. Thus, IF phosphorylation appears to be one of the most predominant strategies in coordinating intracellular organization of the IF network.
Adherens junctions in the Drosophila embryo: The role of E‐cadherin in their establishment and morphogenetic function
Authors: Knust Elisabeth , Leptin Maria
Published: February 2005

The integrity of epithelia depends largely on specialised adhesive structures, the adherens junctions. Several of the components required for building these structures are highly conserved between vertebrates and insects (e.g. E‐cadherin and α‐ and β‐catenin), while others have so far been found only in invertebrates (e.g. crumbs). Two recent papers(1,2) show that the Drosophila E‐cadherin is encoded by the gene shotgun. Phenotypic analyses of shotgun as well as armadillo (β‐catenin) and crumbs mutants provide new insights into the mechanisms by which adherens junctions are built and, further, show that the requirement for E‐cadherin largely depends on the morphogenetic activity of an epithelium.
DNA elements responsive to auxin
Authors: Abel Steffen , Ballas Nurit , Wong Lu‐Min , Theologis Athanasios
Published: February 2005

Genes induced by the plant hormone auxin are probably involved in the execution of vital cellular functions and developmental processes. Experimental approaches designed to elucidate the molecular mechanisms of auxin action have focused on auxin perception, genetic dissection of the signaling apparatus and specific gene activation. Auxin‐responsive promoter elements of early genes provide molecular tools for probing auxin signaling in reverse. Functional analysis of several auxin‐specific promoters of unrelated early genes suggests combinatorial utilization of both conserved and variable elements. These elements are arranged into autonomous domains and the combination of such modules generates uniquely composed promoters. Modular promoters allow for auxin‐mediated transcriptional responses to be revealed in a tissue‐ and development‐specific manner.
The neutral theory is dead. The current significance and standing of neutral and nearly neutral theories
Authors: Ohta Tomoko
Published: February 2005

Comparative studies of DNA sequences provide opportunities for testing the neutral and the selection theories of molecular evolution. In particular, the separate estimation of the numbers of synonymous and nonsynonymous substitutions is a powerful tool for detecting selection of the latter. The difference in the patterns of these two types of substitutions of mammalian genes turned out to be in accord with the slightly deleterious or nearly neutral mutation theory for nonsynonymous changes. Interaction systems at the amino acid level were suggested to be responsible for such nearly neutral, or very weak, selection. Synonymous substitutions are not strictly neutral, but because of their minute effect, random drift predominates such that the rate of substitution is only slightly less than the completely neutral prediction. It was concluded that the strictly neutral theory has not held up as well as the nearly neutral theory, yet remains invaluable as a null hypothesis for detecting selection. On the other hand, the main difference between the nearly neutral and the traditional selection theories is that the former predicts rapid evolution in small populations, whereas the latter predicts rapid evolution in large populations.
Connexins in mammalian heart function
Authors: Gros Daniel B. , Jongsma Habo J.
Published: February 2005

In heart, the propagation of electrical activity is mediated by intercellular channels, referred to as junctional channels, aggregated into gap junctions and localised between myocytes. These channels consist of structurally related transmembrane proteins, the connexins, three of which (CX43, CX40 and CX45) have been shown to be associated with the myocytes of mammalian heart; a fourth, CX37, was detected exclusively in endothelial cells. In this paper, we review the recent data dealing with the topographical heterogeneity of expression of these connexins in the different cardiac tissues and the unique conductance properties of the channels they form, and attempt to assess the role played by each connexin and the consequences of their multiplicity in the propagation of action potentials.
Signaling mechanisms mediating synapse formation
Authors: Wallace Bruce G.
Published: February 2005

Recent experiments have begun to decipher the molecular dialog that mediates differentiation at sites of synaptic between neurons and their targets. It had been hypothesized that the protein agrin is released by axon terminals at embryonic neuromuscular junctions and binds to a receptor on the myofiber surface to trigger postsynaptic differentiation. Now a genetic ‘Knockout’ experiment has confirmed the essential role of agrin in signaling between developing nerve and muscle(1). A second ‘knockout’ has shown that the muscle‐specific receptor tyrosine kinase MuSK is a critical element in the agrin‐induced signaling cascade(2). Additional results suggest that MuSK may comprise a portion of the agrin receptor(3).
Cell proliferation control in Drosophila: Flies are not worms
Authors: Bryant Peter J.
Published: February 2005

The development of organs during animal development requires the allocation of appropriate numbers of cells to each part of the structure. Yet in Drosophila the patterns of cell proliferation can be quite different from one individual to the next, and in fact can be altered experimentally without altering final morphology. The developing pattern seems to control proliferation, rather than the other way around. Even though the pattern of proliferation is variable, there is some order to it. A recent paper(1) shows that small clusters of cells in developing cell populations are in mitotic synchrony, but that the synchrony is transient. What is the significance of this mitotic synchrony?
Invertebrate gerontology: The age mutations of Caenorhabditis elegans
Authors: Lithgow Gordon J.
Published: February 2005

Ageing is a complex phenomenon which remains a major challenge to modern biology. Although the evolutionary biology of ageing is well understood, the mechanisms that limit lifespan are unknown. The isolation and analysis of single‐gene mutations which extend lifespan (Age mutations) is likely to reveal processes which influence ageing. Caenorhabditis elegans is the only metazoan in which Age mutations have been identified. The Age mutations not only prolong life, but also confer a complex array of other phenotypes. Some of these phenotypes provide clues to the evolutionary origins of these genes while others allude to mechanisms of lifespan‐extension. Many of the Age genes interact and share a second common phenotype, that of stress resistance. Rather than invertebrate ageing being determined by a ‘clock mechanism’, a picture is emerging of ageing as a non‐adaptive process determined, in part, by resistance to intrinsic stress mediated by stress‐response genes.
Striving for atomic resolution in biomolecular topography: The scanning force microscope (SFM)
Authors: Schaper Achim , Jovin Thomas M.
Published: February 2005

The invention in 1986 of scanning force microscopy (SFM) provided a new and powerful tool for the investigation of biological structures. SFM yields a three‐dimensional view at nanometer resolution of the surface topography associated with biological objects. The potential for imaging either macromolecules or biomolecules and cells under native (physiological) conditions is currently being exploited to obtain functional information at the molecular level. In addition, the forces involved in individual bimolecular interactions are being assessed under static and dynamic conditions. In this report we focus on the imaging capability of the SFM. The rather broad spectrum of applications represented is intended to orient the prospective user of biological SFM.
DNA rearrangements and mating‐type determination in Paramecium tetraurelia
Authors: Forney James
Published: February 2005

Ciliated protozoa have separate germline and somatic nuclei, yet unlike larger organisms, both nuclei reside in the same cytoplasm. The micronuclei contain the germline and the macronucleus is the somatic nucleus. Thousands of DNA elements are normally removed from the micronuclear genome as it forms a new macronucleus during each sexual cycle. A recent study directly links the excision of these internal eliminated sequences (IESs) to mating type determination by showing that a pleiotropic mutation affecting mating type also prevents the excision of an IES from a surface protein gene(1). Remarkably, once the IES is present in the old macronucleus it prevents excision of that specific IES during formation of the next macronucleus.