bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractRas 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

AbstractPassage 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

AbstractThree 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

AbstractNumerous 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

AbstractIn 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

AbstractSupernumerary 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

AbstractGenetic 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

AbstractThe 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

AbstractTumor 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

AbstractPolycystic 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

AbstractRecent 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

AbstractNormal 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

AbstractGenomic 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

AbstractFinding 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

AbstractThe 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

AbstractAll 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

AbstractActivation 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

AbstractThe 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

AbstractThe 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.
Dorsoventral axis inversion: A phylogenetic perspective
Authors: Lacalli Thurston 
Published: February 2005

AbstractRecent 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

AbstractTelomeres 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

AbstractThe 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

AbstractTranscription 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.