bluuebunny/crossref_metadata_2025 huggingface dataset:
Inherited sensitivity to X‐rays in man
Authors: Thacker John
Published: February 2005

Ataxia‐telangiectasia (A‐T), an inherited disorder giving radiation sensitivity and cancer‐proneness, is discussed in terms of a defect in ability to repair DNA damage. A new assay using damaged recombinant DNA molecules suggests that the fidelity of repair of DNA double‐strand breaks is reduced in an A‐T cell line. Specific chromosomal changes in some A‐T patients appear to be associated with cancer induction, and it is suggested that these could be linked to a DNA repair‐fidelity defect. However, a general correlation between radiosensitivity and cancer‐proneness is difficult to establish at present, partly because of diversity in radiosensitivity in the normal population.
Invertebrate cytokines: The phylogenetic emergence of interleukin‐1
Authors: Beck Gregory , O'Brien Robert F. , Habicht Gail S.
Published: February 2005

Cytokines are polypeptides released by activated vertebrate blood cells which have profound effects on other blood cells and which have hormone‐like properties affecting other organ systems as well. In recent years a wide variety of these mediators has been isolated and characterized. Many of these molecules have subsequently been cloned and expressed in E. coli. The tremendous importance of these proteins to host immune and non‐specific defense systems along with the striking similarities of their properties among different species suggested to us that cytokines may have been proteins that have been conserved through evolution. Investigations of the evolution of cytokines will help us decipher the complex cellular, humoral and molecular interactions that regulate host defenses. Studies of the invertebrates will shed light on the phylogenetic emergence of these molecules as well.
Generation of multiple N‐CAM polypeptides from a single gene
Authors: Walsh Frank S. , Dickson George
Published: February 2005

The neural cell adhesion molecule (N‐CAM) is believed to be a key regulator of adhesive events in the nervous system and skeletal muscle. The recent isolation of N‐CAM cDNAs from different tissues has identified a high degree of diversity in primary amino acid sequence between different isoforms. In this article, we review these recent studies and discuss methods for unravelling the functional consequences of the generation of multiple N‐CAM polypeptides using gene transfection approaches.
The biosynthetic potential of plant roots
Authors: Signs Mark W. , Flores Hector E.
Published: February 2005

The contribution of roots to the biology of the whole plant is being reevaluated in the light of classical and recent findings. In addition to their role in water and nutrient uptake and in symbiotic associations, plant roots also synthesize a remarkable variety of secondary metabolites. These chemicals, many of which are used as pharmaceuticals, agrichemicals, flavors, dyes, or fragrances, may help the plant cope with biotic and abiotic stress. Root cultures are being used as experimental systems to explore both root‐specific secondary metabolites and their biological significance. They may also provide future systems for commercial production of plant specialty chemicals.
Phylogenetic distribution and function of arylalkylamine N‐acetyltransferase
Authors: Smith Timothy J.
Published: February 2005

Amine acetylation is a diverse topic with importance to the regulation of several physiological processes as well as the metabolism of drugs and environmental chemicals. Arylalkylamine N‐acetyltransferase is widely distributed in several species, where this enzyme plays an important role in the seasonal regulation of reproduction and photoperiodism in vertebrates through the pathway of melatonin formation. In insects, this enzyme is involved in monoamine neurotransmitter inactivation and the formation of catecholamine intermediates necessary for sclerotization of the insect cuticle.
Regulation of cell‐type‐specific transcription and differentiation of the pituitary
Authors: Sharp Z. Dave , Cao Zhaodan
Published: February 2005

The transcription of rat prolactin and growth hormone genes in vitro requires a pituitary transcription factor, specific to certain cell types in the pituitary, which currently appears to be the PUF‐I/Pit‐1/GHF‐1 protein. This factor binds to cis‐regulatory elements in the 5′ region of both genes and exerts a positive influence on transcription initiation presumably by interacting with general transcription factors. The PUF‐I/Pit‐1/GHF‐1 transcriptional regulatory protein probably has an important role in not only the differentiation of the pituitary lactotroph/somatotroph cell lineage; it is also expressed in the early development of the nervous system but its function there is less well documented. It appears to be one member of a family of trans‐activator proteins involved in differential gene expression in several cell types.
Transcriptional regulation of the Drosophila segmentation gene fushi tarazu (ftz)
Authors: Dearolf Charles R. , Topol Joanne , Parker Carl S.
Published: February 2005

ftz is one of the ‘pair rule’ segmentation genes of Drosophila melanogaster, and is an important component of the segmentation process in the fruit fly. We discuss the transcriptional mechanism which causes ftz to be expressed in a seven stripe pattern during embryogenesis.
Determination of cell fate in sea urchin embryos
Authors: Livingston Brian T. , Wilt Fred H.
Published: February 2005

Classical embryological studies have provided a great deal of information on the autonomy and stability of cell fate determination in early sea urchin embryos. However, these studies were limited by the tools available at the time, and the interpretation of the results of these experiments was limited by the lack of information available at the molecular level. Recent studies which have re‐examined classical experiments at the molecular level have provided important new insights into the mechanism of determination in sea urchins, and require us to re‐evaluate some long standing theories on the process of differentiation.
Environmental stimuli and transcriptional activity generate transient changes in DNA torsional tension
Authors: Saavedra Raul A.
Published: February 2005

Transient changes in DNA torsional tension are generated by environmental stimuli and transcriptional activity. In eukaryotic cells, these changes can only be accommodated by a chromatin structure that is flexible. This property of chromatin may be essential to the regulation of eukaryotic gene activity.
My favourite molecule: Discovery of the nucleolar targeting signal
Authors: Hatanaka Masakazu
Published: February 2005

The discovery of the signal peptides that direct proteins to localize at the nucleolus is described here. The nucleolar targeting signal termed the NOS consists of clustered basic amino acids organized such that a portion also functions as the nuclear transporting signal. Although a NOS has been identified within the regulatory genes of human retroviruses, HTLV‐I and HIV‐I, signals of similar function in cellular proteins – such as heat shock proteins – may be induced through the configurational change of protein structure by heat or stress.
The synapsins and the regulation of synaptic function
Authors: Bähler Martin , Benfenati Fabio , Valtorta Flavia , Greengard Paul
Published: February 2005

Synapsins I and II are a family of synaptic vesicle‐associated phosphoproteins involved in the short‐term regulation of neurotransmitter release. In this review, we discuss a working model for the molecular mechanisms by which the synapsins act. We propose that synapsin I links synaptic vesicles to actin filaments in the presynaptic nerve terminal and that these interactions are modulated by the reversible phosphorylation of synapsin I through various signal transduction pathways. The high degree of homology between the synapsins suggests that some of the functional properties of synapsin I are also shared by synapsin II.
Genetic control of cell communication in C. elegans development
Authors: Maine Eleanor M. , Kimble Judith
Published: February 2005

Cell communication is crucial for many aspects of growth and differentiation during the development of the nematode Caenorhabditis elegans. Two genes, glp‐1 and lin‐12, mediate a number of known cell–cell interactions. Genetic and molecular analyses of these two genes lead to the conclusion that they are structurally and functionally related. We summarize these studies as well as those involving the identification of other genes that interact with glp‐1 and / or lin‐12.
Inherited disorders of vitamin B12 utilization
Authors: Rosenblatt David S. , Cooper Bernard A.
Published: February 2005

Inborn errors of vitamin B12 (cobalamin) metabolism are associated with homocystinuria and methylmalonic aciduria, either alone or in combination. A number of these disorders have provided the first evidence for the existence of important steps in the transport or metabolism of cobalamin in eukaryotic cells. Eight complementation classes have been defined on the basis of somatic cell hybridization studies. Although the majority of patients present in infancy or early childhood, some are not diagnosed until adolescence or later. For some of these disorders, prenatal diagnosis and therapy with cobalamin during pregnancy has been attempted. Although only males have been described with cblE disease, all of these disorders are presumed to be autosomal recessive in inheritance. The clinical and laboratory aspects of the different complementation classes (cblA–cblG) are reviewed here.
Cell‐cell adhesion molecules in Dictyostelium
Authors: Siu Chi‐Hung
Published: February 2005

Multicellularity in the cellular slime mold Dictyostelium discoideum is achieved by the expression of two types of cell–cell adhesion sites. The EDTA‐sensitive adhesion sites are expressed very early in the developmental cycle and a surface glycoprotein of 24000 Da is known to be responsible for these sites. The EDTA‐resistant contact sites begin to accumulate on the cell surface at the aggregation stage of development. Several glycoproteins have been implicated in the EDTA‐resistant type of cell–cell binding and the best characterized one has an Mr of 80000 (gp80). gp80 mediates cell–cell binding via homophilic interaction and its cell binding site has been mapped to an octapeptide sequence. The mechanism by which gp80 mediates cell–cell adhesion will be discussed.
Problems And Paradigms: Metaphors and the role of genes in development
Authors: Nijhout H. F.
Published: February 2005

In describing the flawless regularity of developmental processes and the correlation between changes at certain genetic loci and changes in morphology, biologists frequently employ two metaphors: that genes ‘control’ development, and that genomes embody ‘programs’ for development. Although these metaphors have an admirable sharpness and punch, they lead, when taken literally, to highly distorted pictures of developmental processes. A more balanced, and useful, view of the role of genes in development is that they act as suppliers of the material needs of development and, in some instances, as context‐dependent catalysts of cellular changes, rather than as ‘controllers’ of developmental progress and direction. The consequences of adopting this alternative view of development are discussed.
Puffs and gene regulation — molecular insights into the Drosophila ecdysone regulatory hierarchy
Authors: Thummel Carl S.
Published: February 2005

Sixteen years ago, Michael Ashburner and his colleagues proposed a hierarchical model for the genetic control of polytene chromosome puffing by the steroid hormone ecdysone. The recent molecular isolation and characterization of three early ecdysone‐inducible genes has confirmed many aspects of this model — these genes are directly induced by ecdysone, repressed by ecdysone‐induced proteins, and appear to encode DNA binding regulatory proteins. The three early genes are also remarkably similar in structure. They are all unusually long and complex, with multiple transcripts that direct the synthesis of several related proteins from each locus. Proteins encoded by two of the early genes bind to both early and late ecdysone‐induced puffs, implying that they are key regulators in the hierarchy.
Neural repair and glial proliferation: Parallels with gliogenesis in insects
Authors: Smith Peter J. S. , Shepherd David , Edwards John S.
Published: February 2005

There is a growing recognition, stemming from work with both vertebrates and invertebrates, that the capacity for neuronal regeneration is critically dependent on the local microenvironment. That environment is largely created by the non‐neuronal elements of the nervous system, the neuroglia. Therefore an understanding of how glial cells respond to injury is crucial to understanding neuronal regeneration. Here we examine the process of repair in a relatively simple nervous system, that of the insect, in which it is possible to define precisely the cellular events of the repair process. This repair is rapid and well organised; it involves the recruitment of blood cells, the division of endogenous glial elements and, possibly, migration from pre‐existing glial pools in adjacent ganglia. There are clear parallels between the events of repair and those of normal glial development. It seems likely that the ability of the insect central nervous system to repair resides in the retention of developmental capacities throughout its life and that damage results in the activation of this potential.
The ‘A rule’ of mutagen specificity: A consequence of DNA polymerase bypass of non‐instructional lesions?
Authors: Strauss Bernard S.
Published: February 2005

The replicative bypass of lesions in DNA and the induction of mutations by agents which react with DNA to produce damaged bases can be understood on the basis of a simple kinetic model. Bypass can be analyzed by separately considering three processes: (a) addition of a base opposite a lesion, (b) a proofreading excision process, and (c) a rate limiting elongation step. Adenine nucleotides are preferentially added opposite many lesions making it possible to predict mutational specificity. Replicative bypass (translesion synthesis) is dependent on modulation of proofreading exonuclease activity but loss of exonuclease activity alone is not sufficient to ensure bypass. Frameshift mutation is the result of the failure of translesion synthesis accompanied by rearrangement of the template, particularly at repetitive sites.
High frequency force generation in outer hair cells from the mammalian ear
Authors: Holley Matthew
Published: February 2005

Mammalian outer hair cells generate mechanical forces at acoustic frequencies and can thus amplify the sound stimulus within the inner ear. The mechanism of force generation depends upon the plasma membrane potential but not upon either calcium or ATP. Forces are generated in the lateral cortex along the full length of the cell. The cortex includes a two‐dimensional cytoskeletal lattice composed of circumferential filaments 6–7 nm thick that are cross‐linked by filaments 3–4 nm thick and 40–60 nm long. The two filament types may, respectively, be actin and some form of spectrin. The lattice reinforces the cylindrical shape of the cell and permits limited changes in length. Beneath it lie the lateral cisternae, a regular system of multi‐layered membranes. Force–generation may depend upon voltage‐dependent shape changes in proteins that lie either in the plasma membrane or in the cytoskeletal lattice.
Actin filaments and photoreceptor membrane turnover
Authors: Williams David S.
Published: February 2005

The shape and turnover of photoreceptor membranes appears to depend on associated actin filaments. In dipterans, the photoreceptor membrane is microvillar. It is turned over by the addition of new membrane at the bases of the microvilli and by subsequent shedding, mostly from the distal ends. Each microvillus contains actin filaments as a component of its cytoskeletal core. Two myosin I‐like proteins co‐localize with the actin filaments. It is suggested that one of the myosin I‐like proteins might be linked to the microvillar membrane. By interacting with the actin filaments, this motor should move the membrane of a microvillus in a distal direction, thus providing a possible mechanism for the turnover of the membrane.

A vertebrate photoreceptor cell contains a small cluster of actin filaments in its connecting cilium at the site where new transductive disk membranes are formed. Disruption of the actin filaments perturbs disk morphogenesis. The most likely explanation for this perturbation is that the process of initiating a new disk is inhibited. Conventional myosin (myosin II) is found in the connecting cilium with the same distribution as actin. A simple model is proposed to illustrate how the actin–myosin system of the connecting cilium might function to initiate the morphogenesis of a disk membrane.
Exons – original building blocks of proteins?
Authors: Patthy László
Published: February 2005

In a recent paper, Walter Gilbert's group has estimated the number of original exons from which all extant proteins might have been constructed. The approach used is subjected to a critical analysis here. It is shown that there are flawed assumptions about both the mechanism and generality of exon‐shuffling and in the sequence comparison procedures employed, the latter failing to distinguish chance similarity from similarity due to common ancestry. These methodological errors lead to the omission of many known cases of exonshuffling and the inclusion of others which may not be genuine. In consequence, the analysis from the Gilbert group cannot give a reliable estimate of those modules that actually participated in exon‐shuffling and provides no information on the number of protein archetypes that did not participate in these processes.
Actin in the Drosophila embryo: Is there a relationship to developmental cue localization?
Authors: Bearer Elaine L.
Published: February 2005

Recent genetic manipulations have revealed that the cytoplasm of the early Drosophila embryo contains localized information that specifies the future embryonic axes. It is the restricted distribution or activity of particular gene products, either messenger RNA or protein, that is crucial for this specification. While some of the genes responsible for this information have been seqenced and the nature and distribution of their products examined, it is not known how this localization is established or maintained. The actin‐based cytoskeleton is a likely candidate for the formation of a cytomatrix that would allow such distributions and yet no direct evidence has yet been found that implicates actin in positional cue localization. In this review I summarize what is known about actin filament behavior. in Drosophila embryos and compare it to the distribution of positional cues. My purpose is to juxtapose these two bodies of information such that the relationship between them may be revealed.
Eukaryotic DNA repair: Glimpses through the yeast Saccharomyces cerevisiae
Authors: Friedberg Errol C.
Published: February 2005

Eukaryotic cells are able to mount several genetically complex cellular responses to DNA damage. The yeast Saccharomyces cerevisiae is a genetically well characterized organism that is also amenable to molecular and biochemical studies. Hence, this organism has provided a useful and informative model for dissecting the biochemistry and molecular biology of DNA repair in eukaryotes.
Gene expression, cellular diversification and tumor progression to the metastatic phenotype
Authors: Nicolson Garth L.
Published: February 2005

Alterations in the expression of certain genes or in their products can render benign tumor cells metastatic. Experimentally this has been quickly performed by transferring dominantly acting oncogenes such as c‐H‐rasEJ into susceptible cells, but in vivo such a rapid qualitative change in a dominantly acting oncogene occurs only rarely, and progression to highly metastatic phenotypes is thought to occur through a slow stepwise process. Such slow changes can be reversible and need not involve known dominantly acting oncogenes, consistent with clinical observations. An important element of the natural progression of tumors to malignancy may be their ability to circumvent microenvironmental controls that regulate growth and cellular diversity and to evolve into heterogeneous phenotypes, a process that appears to involve mainly quantitative changes in gene expression but which can be rapidly stimulated in cell culture by the introduction of a dominantly acting oncogene. It is proposed that the highly malignant cells that have slowly evolved in vivo with only a few qualitative gene changes have undergone extensive cycles of diversification and accumulation of quantitative changes in the expression of genes that encode products that are related to malignancy and metastasis. Thus, highly malignant cellular phenotypes can arise quickly through specific qualitative changes in critical controlling genes or more slowly by less critical qualitative genetic changes, coupled with cellular diversification and accumulation of quantitative changes in gene expression.
Expression patterns of mouse hox genes: Clues to an understanding of developmental and evolutionary strategies
Authors: Gaunt Stephen J.
Published: February 2005

Expression patterns of Antennapedia‐like homeogenes in the mouse embryo show many similarities to those of their homologues in Drosophila. It is argued here that homeogenes may regulate development of the body plan in mouse by mechanisms similar to those used in Drosophila. In particular, they may differentially specify positional address of cell groups within lineage compartments along the body axes. In vertebrates, a single ancestral homeogene cluster has become duplicated to give four separate clusters. Comparisons of homeogene expression patterns between different clusters of the mouse suggest ways in which duplication has permitted development of a more complex body plan. Cluster duplication may therefore have provided a selective advantage during vertebrate evolution.
The biology of cancer metastasis or, ‘you cannot fix it if you do not know how it works’
Authors: Fidler Isaiah J.
Published: February 2005

The major cause of death from cancer is the relentless growth of metastases that are resistant to conventional therapy. The pathogenesis of a metastasis is complex and requires that tumor cells complete a sequence of potentially lethal interactions with various host factors. The finding in 1973 that metastasis is selective process and the finding in 1977 that malignant neoplasms are heterogeneous and contain few preexisting metastatic subpopulations have added a new dimension to our understanding of cancer and its spread. This understanding is now contributing to the design of better therapies against disseminated metastasis.
Specification of cell fate in the developing eye of Drosophila
Authors: Basler Konrad , Hafen Ernst
Published: February 2005

Determination of cell fate in the developing eye of Drosophila depends on a precise sequence of cellular interactions which generate the stereotypic array of ommatidia. In the eye imaginal disc, an initially unpatterned epithelial sheath of cells, the first step in this process may be the specification of R8 photoreceptor cells at regular intervals. Genes such as Notch and scabrous, known to be involved in bristle development, alos participate in this process, suggesting that the specification of ommatidial founder cells and the formation of sensory organs in the adult epidermis may involve a similar mechanism, that of lateral inhibition. The subsequent steps of ommatidial assembly, following R8 assignment, involve a different mechanism: Undetermined cells read their position based on the contacts they make with neighbors that have already begun to differentiate. The development of the R7 photoreceptor cell, one of the eight photoreceptor cells in the ommatidium, is best understood. An important role seems to be played by sevenless, a receptor tyrosine kinase on the surface of the R7 precursor. It transmits the positional information– most likely encoded by the boss protein on the neighboring R8 cell membrane – into the cell via its tyrosine kinase, which activates a signal transduction cascade. Constitutive activation of the sevenless kinase by overexpression of an N‐terminally truncated form results in the diversion of other ommatidial cells into the R7 pathway suggesting that activation of the sevenless signalling pathway is sufficient to specify R7 development. Genetic dissection of this pathway should therefore identify components of a signalling cascade activated by a tyrosine kinase.
The prenylation of proteins
Authors: Sinensky Michael , Lutz Robert J.
Published: February 2005

The prenylated proteins represent a newly discovered class of post‐translationally modified proteins. The known prenylated proteins include the oncogene product p21ras and other low molecular weight GTP‐binding proteins, the nuclear lamins, and the γ subunit of the heterotrimeric G proteins. The modification involves the covalent attachment of a 15‐carbon (farnesyl) or 20‐carbon (geranylgeranyl) isoprenoid moiety in a thioether linkage to a carboxyl terminal cysteine. The nature of the attached substituent is dependent on specific sequence information in the carboxyl terminus of the protein. In addition, prenylation entrains other post‐translational modifications forming a reaction pathway. In this article, we review our current understanding of the biochemical reactions involved in prenylation and discuss the possible role of this modification in the control of cellular functions such as protein maturation and cell growth.
Chromosome motion in mitosis
Authors: Gorbsky Gary J.
Published: February 2005

The nature of the forces that move chromosomes in mitosis is beginning to be revealed. The kinetochore, a specialized structure situated at the primary constriction of the chromosome, appears to translocate in both directions along the microtubules of the mitotic spindle. One or more members of the newly described families of microtubule motor molecules may power these movements. Microtubules of the mitotic spindle undergo rapid cycles of assembly and disassembly. These microtubule dynamics may contribute toward generating force and regulating direction in chromosome movement.
The end of the message: 3'– end processing leading to polyadenylated messenger RNA
Authors: Wahle Elmar
Published: February 2005

Almost all messenger RNAs carry a polyadenylate tail that is added in a post‐transcriptional reaction. In the nuclei of animal cells, the 3'‐end of the RNA is formed by endonucleolytic cleavage of the primary transcript at the site of poly (A) addition, followed by the polymerisation of the tail. The reaction depends on specific RNA sequences upstream as well as downstream of the polyadenylation site. Cleavage and polyadenylation can be uncoupled in vitro. Polyadenylation is carried out by poly(A) polymerase with the aid of a specificity factor that binds the polyadenylation signal AAUAAA. Several aditional factors are required for the initial cleavage. A newly discovered poly(A)‐binding protein stimulates poly(A) tail synthesis and may be involved in the control of tail length. Polyadenylation reactions different from this scheme, either in other organisms or under special physiological circumstances, are discussed.
What determines the instability of c‐myc proto‐oncogene mRNA?
Authors: Laird‐Offringa Ite A.
Published: February 2005

The c‐myc proto‐oncogene is believed to be involved in the regulation of cell growth and differentiation. Deregulation of this gene, resulting in an inappropriate increase of gene product, can contribute to cancer formation. One of the ways in which the expression of the c‐myc gene can be deregulated is by the stabilization of the labile c‐myc mRNA. The rapid degradation of the c‐myc transcript appears to be mediated by at least two distinct regions in the mRNA. One lies in the 3' untranslated region, and presumably consists of (A+U)‐rich sequences. The other lies in the C‐terminal part of the coding region and colocalizes with sequences encoding protein‐dimerization motifs. The exact mechanism by which the destabilizing elements function is not yet clear. Shortening of the poly(A) tail of the c‐myc message appears to precede degradation of the transcript. When translation is blocked, this shortening is slowed down and the mRNA is stabilized. This suggests that deadenylation is required before degradation of the mRNA body can take place.
Problems and paradigms: Dynamic lipid‐bilayer heterogeneity: A mesoscopic vehicle for membrane function?
Authors: Mouritsen Ole G. , Jørgensen Kent
Published: February 2005

The lipid‐bilayer component of cell membranes is an aqueous bimolecular aggregate characterized by a heterogeneous lateral organization of its molecular constituents. The heterogeneity may be sustained statically as well as dynamically. On the basis of recent experimental and theoretical progress in the study of the physical properties of lipid‐bilayer membranes, it is proposed that the dynamically heterogeneous membrane states are important for membrane functions such as transport of matter across the membrane and enzymatic activity. The heterogeneous membrane states undergo significant structural changes in response to changes in compositional, thermodynamic, and environmental conditions. The diverse effects of a variety of molecular Compounds interacting with membranes, such as Cholesterol and drugs like anaesthetics, may be understood in terms of the ability of these compounds to affect and modulate the dynamic membrane heterogeneity.
What the papers say: Protein folding pathways determined using disulphide bonds
Authors: Creighton Thomas E.
Published: February 2005

The best‐characterized model pathway of protein folding, that of disulphide bond formation in the small protein BPTI, has been questioned recently. A reinvestigation of that pathway, using alternative methods, concluded that the intermediates with non‐native disulphide bonds accumulated to lower levels than previously had been observed(17). On this basis, a revised pathway was proposed that simply omitted those intermediates. Even if totally correct, however, the new observations are not inconsistent with the important characteristics of the original pathway and even confirmed many of them. Certain crucial observations that were the experimental basis for the original pathway were ignored, and these observations invalidate the revised pathway.
Evolution of alternate modes of development in ascidians
Authors: Jeffery William R. , Swalla Billie J.
Published: February 2005

Ascidians have evolved alternate modes of development in which the conventional tadpole larva is remodeled or eliminated. Adultation, the precocious development of adult features in the larval head, is caused by superimposing the larval and adult differentiation programs. Caudalization, the addition of muscle cells to the larval tail, is caused by enhancing muscle induction or increasing the number of muscle cell divisions before terminal differentiation. Adultation and caudalization are correlated with increased egg size, suggesting dependence on maternal processes. Anural development, the elimination of the larval stage, is caused by maternal and zygotic events resulting in abbreviation and deletion of larval developmental programs. An example of a maternal change in anural species is the modification of the egg cytoskeleton during oogenesis, whereas a zygotic change may involve altered cell interactions during embryogenesis. Interspecific hybridization experiments suggest that some aspects of anural development may be caused by loss‐of‐function mutations. The dissociation of developmental programs is a key process in changing the mode of development in ascidians.
Problems and paradigms: Redundancies, development and the flow of information
Authors: Tautz Diethard
Published: February 2005

There is increasing evidence for the wide‐spread existence of functionally redundant genetic pathways in developmental processes. However, both their significance and manner of evolution are still matters of debate. I will argue here that redundancy of gene actions may, in fact, be a necessary requirement for the development and evolution of complex life forms. One can view development as a process that transmits information from the egg to the adult organism. Transmission of information is, however, always an error‐prone process, which can only be safeguarded by including redundancies in the message. Molecular examples for well analysed redundant processes indicate that redundancies may best be understood within a conceptual framework of overlaps between different gene functions.
Problems and paradigms: Hoemeobox genes in vertebrate evolution
Authors: Holland Peter
Published: February 2005

A wide range of anatomical features are shared by all vertebrates, but absent in our closest invertebrate relatives. The origin of vertebrate embryogenesis must have involved the evolution of new regulatory pathways to control the development of new features, but how did this occur? Mutations affecting regulatory genes, including those containing homeobox sequences, may have been important: for example, perhaps gene duplications allowed recruitment of genes to new roles. Here I ask whether comparative data on the genomic organization and expression patterns of homeobox genes support this hypothesis. I propose a model in which duplications of particular homeobox genes, followed by the acquisition of gene‐specific secondary expression domains, allowed the evolution of the neural crest, extensive organogenesis and craniofacial morphogenesis. Specific details of the model are amenable to testing by extension of this comparative approach to molecular embryology.
The molecular basis of the type 1 glycogen storage diseases
Authors: Burchell Ann
Published: February 2005

Microsomal glucose‐6‐phosphatase catalyses the last step in liver glucose production. Glucose‐6‐phosphatase deficiency, now termed type 1 glycogen storage disease, was first described almost 40 years ago but until recently very little was known about the molecular basis of the various type 1 glycogen storage diseases. Recently we have shown that at least six different proteins are needed for normal glucose‐6‐phosphatase activity in liver. Four of the proteins have been purified and three cloned. Study of the type 1 glycogen storage diseases has stimulated investigations of the mechanisms of small molecule transport across the endoplasmic reticulum membrane and demonstrated the existence of novel endoplasmic reticulum transport proteins for glucose and phosphate.
The matrix‐degrading metalloproteinases
Authors: Matrisian Lynn M.
Published: February 2005

The matrix‐degrading metalloproteinases are an intriguing family of enzymes that have evolved to digest specific extracellular matrix components. The expression of these enzymes is very highly regulated and can be controlled transcriptionally by a number of growth factors, tumor promoters, oncogenes, and hormones. It is suggested that the coordinated regulation of matrix metalloproteinases and their inhibitors by these agents modify the integrity of the extracellular matrix. These modifications may, at least in part, be responsible for mediating the effects of these factors on complex physiological processes.
Is calpain activity regulated by membranes and autolysis or by calcium and calpastatin?
Authors: Goll Darrel E. , Thompson Valery F. , Taylor Richard G. , Zalewska Teresa
Published: February 2005

Although the Ca2+‐dependent proteinase (calpain) system has been found in every vertebrate cell that has been examined for its presence and has been detected in Drosophila and parasites, the physiological function(s) of this system remains unclear. Calpain activity has been associated with cleavages that alter regulation of various enzyme activities, with remodeling or disassembly of the cell cytoskeleton, and with cleavages of hormone receptors. The mechanism regulating activity of the calpain system in vivo also is unknown. It has been proposed that binding of the calpains to phospholipid in a cell membrane lowers the Ca2+ concentration, [Ca2+], required for the calpains to autolyze, and that autolysis converts an inactive proenzyme into an active protease. Recent studies, however, show that the calpains bind to specific proteins and not to phospholipids, and that binding to cell membranes does not affect the [Ca2+] required for autolysis. It seems likely that calpain activity is regulated by binding of Ca2+ to specific sites on the calpain molecule, with binding to each site eliciting a response (proteolytic activity, calpastatin binding, etc.) specific for that site. Regulation must also involve an, as yet, undiscovered mechanism that increases the affinity of the Ca2+‐binding sites for Ca2+.
Mammalian origins of replication
Authors: Hamlin Joyce L.
Published: February 2005

It has been almost twenty‐five years since Huberman and Riggs first showed that there are multiple bidirectional origins of replication scattered at ∼100 kb intervals along mammalian chromosomal fibers. Since that time, every conceivable physical property unique to replicating DNA has been taken advantage of to determine whether origins of replication are defined sequence elements, as they are in microorganisms. The most thoroughly studied mammalian locus to date is the dihydrofolate reductase domain of Chinese hamster cells, which will be used as a model to discuss the various methods of investigation. While several laboratories agree on the rough location of the [initiation locus] in this large chromosomal domain, different experimental approaches paint different pictures of the mechanism by which initiation occurs. However, a variety of new techniques and synchronizing agents promises to clarify the picture for this particular locus, and to provide the means for identifying and isolating other origins of replication for comparison.
What have tissue culture studies told us about the development of oligodendrocytes?
Authors: Williams Brenda P. , Price Jack
Published: February 2005

One major success of studying neural cell development in tissue culture has been the discovery of the O‐2A cell. This bipotential cell generates oligodendrocytes or, under certain conditions, a type of astrocyte. This essay considers the evidence that the characteristic properties demonstrated by the O‐2A cells in vitro are an accurate reflection of oligodendrocyte development in vivo.
AMP‐activated protein kinase ‐ An archetypal protein kinase cascade?
Authors: Hardie D. Grahame , Mackintosh Robert W.
Published: February 2005

Mammalian AMP‐activated protein kinase is the central component of a protein kinase cascade which inactivates three key enzymes involved in the synthesis or release of free fatty acids and cholesterol inside the cell. The kinase cascade is activated by elevation of AMP, and perhaps also by fatty acid and cholesterol metabolites. The system may fulfil a protective function, preventing damage caused by depletion of ATP or excessive intracellular release of free lipids, a type of stress response. Recent evidence suggests that it may have been in existence for at least a billion years, since a very similar protein kinase cascade is present in higher plants. This system therefore represents an early eukaryotic protein kinase cascade, which is unique in that it is regulated by intracellular metabolites rather than extracellular signals or cell cycle events.
DNA synthesis control in yeast: An evolutionarily conserved mechanism for regulating DNA synthesis genes?
Authors: Merrill Gary F. , Morgan Brian A. , Lowndes Noel F. , Johnston Leland H.
Published: February 2005

After yeast cells commit to the cell cycle in a process called START, genes required for DNA synthesis are expressed in late G1. Periodicity is mediated by a hexameric sequence, known as a MCB element, present in all DNA synthesis gene promoters. A complex that specifically binds MCBs has been identified. One polypeptide in the MCB complex is Swi6, a transcription factor that together with Swi4 also binds G1 cyclin promoters and participates in a positive feedback loop at START. The finding that Swi6 is directly involved in both START and DNA synthesis gene control suggest a model in which Swi6, activated through its participation in START, serves as the central transcription factor in coordinating late G1 gene expression. The mechanism may be conserved in all eukaryotic cells.
Cyclin synthesis: Who needs it?
Authors: Minshull Jeremy
Published: February 2005

Studies of the G2 to M transition in amphibian oocytes, in combination with in vitro mitotic systems and yeast genetic analysis, have significantly contributed to our understanding of the mechanisms by which M‐phase is regulated. Historically, oocyte maturation has provided a number of valuable initial observations, but the biochemical elucidation of cell cycle control mechanisms has proved more tractable in cell‐free extracts of frog eggs which reproduce aspects of early embryogenic mitosis. Recent experiments examining the importance of protein synthesis in the maturing oocyte have highlighted some important differences between mitosis and meiosis. Additional controls found in meiosis but not embryonic mitosis, are similar to controls found in somatic cells. This suggests that understanding the differences, as well as the similarities, between meiosis in the oocyte and mitosis in the early embryo will help us to learn more about the way in which cells enter and leave mitosis.
The evolutionary history of the first three enzymes in pyrimidine biosynthesis
Authors: Davidson Jeffrey N. , Chen Kuey C. , Jamison Robert S. , Musmanno Lisa A. , Kern Christine B.
Published: February 2005

Some metabolic pathways are nearly ubiquitous among organisms: the genes encoding the enzymes for such pathways must therefore be ancient and essential. De novo pyrimidine biosynthesis is an example of one such metabolic pathway. In animals a single protein called CAD

Abbreviations: CAD, trifunctional protein catalyzing the first three steps of de novo pyrimidine biosynthesis in higher eukaryotes; CPS, carbamyl phosphate synthetase domain; CPSase, carbamyl phosphate synthetase activity; ATC, aspartate transcarbamylase domain; ATCase, aspartate transcarbamylase activity; DHO, dihydroorotase domain; DHOase, dihydroorotase activity; GLN, glutaminase subdomain or subunit of carbamyl phosphate synthetase, GL Nase, glutaminase activity; SYN, synthetase subdomain or subunit of carbamyl phosphate synthetase; SYNase, synthetase activity.

carries the first three steps of this pathway. The same three enzymes in prokaryotes are associated with separate proteins. The CAD gene appears to have evolved through a process of gene duplication and DNA rearrangement, leading to an in‐frame gene fusion encoding a chimeric protein. A driving force for the creation of eukaryotic genes encoding multienzymatic proteins such as CAD may be the advantage of coordinate expression of enzymes catalyzing steps in a biosynthetic pathway. The analogous structure in bacteria is the operon. Differences in the translational mechanisms of eukaryotes and prokaryotes may have dictated the different strategies used by organisms to evolve coordinately regulated genes.
Tyrosine kinase receptors in the control of epithelial growth and morphogenesis during development
Authors: Birchmeier Carmen , Sonnenberg Eva , Weidner K. Michael , Walter Barbara
Published: February 2005

The c‐ros, c‐met and c‐neu genes encode receptor‐type tyrosine kinases and were originally identified because of their oncogenic potential. However, recent progress in the analysis of these receptors and their respective ligands indicate that they do not mediate exclusively mitogenic signals. Rather, they can induce cell movement, differentiation or morphogenesis of epithelial cells in culture. Interestingly, the discussed receptors are expressed in embryonal epithelia, whereas direct and indirect evidence shows that the corresponding ligands are produced in mesenchymal cells. In development, signals given by mesenchymal cells are major driving forces for differentiation and morphogenesis of epithelia; embryonal epithelia are generally unable to differentiate without the appropriate mesenchymal factors. The observed activities of these receptor/ligand systems in cultured cells and their expression patterns indicate that they regulate epithelial differentiation and morphogenesis also during embryogenesis and suggest thus a molecular basis for mesenchymal epithelial interactions.
Early human embryo metabolism
Authors: Leese Henry J. , Conaghan Joe , Martin Karen L. , Hardy Kate
Published: February 2005

Non‐invasive microanalytical methods have been devised to study the energy metabolism of single human preimplantation embryos. Psyruvate, which is added routinely to all media used to culture human embryos, is consumed throughout the preimplantation period, with glucose assuming an increasing role at embryo compaction and blastocyst formation. All of the glucose consumed may be accounted for by the appearance of lactate in the incubation medium. The enzyme hexokinase my be involved in regulating this aerobic glycolysis. There is cosiderable indirect evidence for the utilisation of endogenous as opposed to exogenous energy substrates, the most likely candidate being protein. Information on early human embryo metabolismis likely to find application in a number of areas: these include the improvement of techniques for assisted human conception, notably in the selection of embryos for transfer following In Vitro Fertilisation; the diagnosis of gentic defects at the preimplantation stage; increased undersding of the causes of implantation failure and miscarriage, and the development of novel post‐coital contraceptives.
DNA damage and cell cycle regulation of ribonucleotide reductase
Authors: Elledge Stephen J. , Zhou Zheng , Allen James B. , Navas Tony A.
Published: February 2005

Ribonucleotide reductase (RNR) catalyzes the rate limiting step in the production of deoxyribonucleotides needed for DNA synthesis. In addition to the well documented allosteric regulation, the synthesis of the enzyme is also tightly regulated at the level of transcription. mRNAs for both subunits are cell cycle regulated and inducible by DNA damage in all organisms examined, including E. coli, S. cerevisiae and H. sapiens. This DNA damage regulation is thought to provide a metabolic state that facilitates DNA replicational repair processes. S. cerevisiae also encodes a second large subunit gene, RNR3, that is expressed only in the presence of DNA damage. Genetic analysis of the DNA damage response in S. cerevisiae has shown that RNR expression is under both positive and negative control. Among mutants constitutive for RNR expression are the general transcriptional repression genes, SSN6 and TUP1. Mutations in POL1 and POL3 also activate RNR expression, indicating that the DNA damage sensory network may respond directly to blocks in DNA synthesis. A protein kinase, Dun1, has been identified that controls inducibility of RNR1, RNR2 and RNR3 in response to DNA damage and replication blocks. This result suggests that the RNR genes in S. cerevisiae form a regulon that is coordinately regulated by protein phosphorylation in response to DNA damage.
Endocytosis of growth factor receptors
Authors: Sorkin Alexander , Waters Christopher M.
Published: February 2005

Binding of a growth factor (GF) to its specific receptor on the cell surface causes the initiation of a signal transduction cascade which eventually results in mitosis. GF:receptor complexes are removed from the cell surface via receptor‐mediated endocytosis, a process which involves clathrin‐coated pits. After internalization into the endosomal compartment, a significant pool of GFs and GF receptors escape recycling to the cell surface and are sorted to the degradation pathway. The ligandinduced internalization and lysosomal degradation of GF receptors result in the dramatic loss of surface receptors, a phenomenon termed receptor down‐regulation. In this review, we discuss relevant biochemical, morphological and kinetic studies of the mechanism of GF endocytosis, and the possible role of this process in mitogenic signaling by growth factor receptors.