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  • Prelude to a division.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2008-07-04
    Needhi Bhalla,Abby F Dernburg

    Accurate segregation of chromosomes during meiosis requires physical links between homologs. These links are usually established through chromosome pairing, synapsis, and recombination, which occur during meiotic prophase. How chromosomes pair with their homologous partners is one of the outstanding mysteries of meiosis. Surprisingly, experimental evidence indicates that different organisms have found more than one way to accomplish this feat. Whereas some species depend on recombination machinery to achieve homologous pairing, others are able to pair and synapse their homologs in the absence of recombination. To ensure specific pairing between homologous chromosomes, both recombination-dependent and recombination-independent mechanisms must strike the proper balance between forces that promote chromosome interactions and activities that temper the promiscuity of those interactions. The initiation of synapsis is likely to be a tightly regulated step in a process that must be mechanically coupled to homolog pairing.

    更新日期:2019-11-01
  • TRP channels and pain.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2013-10-09
    David Julius

    Nociception is the process whereby primary afferent nerve fibers of the somatosensory system detect noxious stimuli. Pungent irritants from pepper, mint, and mustard plants have served as powerful pharmacological tools for identifying molecules and mechanisms underlying this initial step of pain sensation. These natural products have revealed three members of the transient receptor potential (TRP) ion channel family--TRPV1, TRPM8, and TRPA1--as molecular detectors of thermal and chemical stimuli that activate sensory neurons to produce acute or persistent pain. Analysis of TRP channel function and expression has validated the existence of nociceptors as a specialized group of somatosensory neurons devoted to the detection of noxious stimuli. These studies are also providing insight into the coding logic of nociception and how specification of nociceptor subtypes underlies behavioral discrimination of noxious thermal, chemical, and mechanical stimuli. Biophysical and pharmacological characterization of these channels has provided the intellectual and technical foundation for developing new classes of analgesic drugs.

    更新日期:2019-11-01
  • Sizing up to divide: mitotic cell-size control in fission yeast.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2015-11-14
    Elizabeth Wood,Paul Nurse

    Schizosaccharomyces pombe is a good model to study cell-size control. These cells integrate size information into cell cycle controls at both the G1/S and G2/M transitions, although the primary control operates at the entry into mitosis. At G2/M there is both a size threshold, demonstrated by the fact that cells divide when they reach 14 μm in length, and also correction around this threshold, evident from the narrow distribution of sizes within a population. This latter property is referred to as size homeostasis. It has been argued that a population of cells accumulating mass in a linear fashion will have size homeostasis in the absence of size control, if cycle time is controlled by a fixed timer. Because fission yeast cells do not grow in a simple linear fashion, they require a size-sensing mechanism. However, current models do not fully describe all aspects of this control, especially the coordination of cell size with ploidy.

    更新日期:2019-11-01
  • Insights into morphology and disease from the dog genome project.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2014-07-26
    Jeffrey J Schoenebeck,Elaine A Ostrander

    Although most modern dog breeds are less than 200 years old, the symbiosis between man and dog is ancient. Since prehistoric times, repeated selection events have transformed the wolf into man's guardians, laborers, athletes, and companions. The rapid transformation from pack predator to loyal companion is a feat that is arguably unique among domesticated animals. How this transformation came to pass remained a biological mystery until recently: Within the past decade, the deployment of genomic approaches to study population structure, detect signatures of selection, and identify genetic variants that underlie canine phenotypes is ushering into focus novel biological mechanisms that make dogs remarkable. Ironically, the very practices responsible for breed formation also spurned morbidity; today, many diseases are correlated with breed identity. In this review, we discuss man's best friend in the context of a genetic model to understand paradigms of heritable phenotypes, both desirable and disadvantageous.

    更新日期:2019-11-01
  • Optogenetic control of cells and circuits.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2011-08-09
    Gero Miesenböck

    The absorption of light by bound or diffusible chromophores causes conformational rearrangements in natural and artificial photoreceptor proteins. These rearrangements are coupled to the opening or closing of ion transport pathways, the association or dissociation of binding partners, the enhancement or suppression of catalytic activity, or the transcription or repression of genetic information. Illumination of cells, tissues, or organisms engineered genetically to express photoreceptor proteins can thus be used to perturb biochemical and electrical signaling with exquisite cellular and molecular specificity. First demonstrated in 2002, this principle of optogenetic control has had a profound impact on neuroscience, where it provides a direct and stringent means of probing the organization of neural circuits and of identifying the neural substrates of behavior. The impact of optogenetic control is also beginning to be felt in other areas of cell and organismal biology.

    更新日期:2019-11-01
  • Membrane protein insertion at the endoplasmic reticulum.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2011-08-02
    Sichen Shao,Ramanujan S Hegde

    Integral membrane proteins of the cell surface and most intracellular compartments of eukaryotic cells are assembled at the endoplasmic reticulum. Two highly conserved and parallel pathways mediate membrane protein targeting to and insertion into this organelle. The classical cotranslational pathway, utilized by most membrane proteins, involves targeting by the signal recognition particle followed by insertion via the Sec61 translocon. A more specialized posttranslational pathway, employed by many tail-anchored membrane proteins, is composed of entirely different factors centered around a cytosolic ATPase termed TRC40 or Get3. Both of these pathways overcome the same biophysical challenges of ferrying hydrophobic cargo through an aqueous milieu, selectively delivering it to one among several intracellular membranes and asymmetrically integrating its transmembrane domain(s) into the lipid bilayer. Here, we review the conceptual and mechanistic themes underlying these core membrane protein insertion pathways, the complexities that challenge our understanding, and future directions to overcome these obstacles.

    更新日期:2019-11-01
  • Membrane-anchored serine proteases in vertebrate cell and developmental biology.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2011-07-05
    Roman Szabo,Thomas H Bugge

    Analysis of vertebrate genome sequences at the turn of the millennium revealed that a vastly larger repertoire of enzymes execute proteolytic cleavage reactions within the pericellular and extracellular environments than was anticipated from biochemical and molecular analysis. Most unexpected was the unveiling of an entire new family of structurally unique multidomain serine proteases that are anchored directly to the plasma membrane. Unlike secreted serine proteases, which function primarily in tissue repair, immunity, and nutrient uptake, these membrane-anchored serine proteases regulate fundamental cellular and developmental processes, including tissue morphogenesis, epithelial barrier function, ion and water transport, cellular iron export, and fertilization. Here the cellular and developmental biology of this fascinating new group of proteases is reviewed. Particularly highlighted is how the study of membrane-anchored serine proteases has expanded our knowledge of the range of physiological processes that require regulated proteolysis at the cell surface.

    更新日期:2019-11-01
  • The role of MeCP2 in the brain.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2011-07-05
    Jacky Guy,Hélène Cheval,Jim Selfridge,Adrian Bird

    Methyl-CpG binding protein 2 (MeCP2) was first identified in 1992 as a protein that binds specifically to methylated DNA. Mutations in the MECP2 gene were later found to be the cause of an autism spectrum disorder, Rett syndrome. Despite almost 20 years of research into the molecular mechanisms of MeCP2 function, many questions are yet to be answered conclusively. This review considers several key questions and attempts to evaluate the current state of evidence. For example, is MeCP2 just a methyl-CpG binding protein? Is it a multifunctional protein or primarily a transcriptional repressor? We also consider whether MeCP2, as a chromosome-binding protein, acts at specific sites within the genome or more globally, and in which cell types it is functionally important. Finally, we consider two alternative views of MeCP2 in the brain: as a regulator of brain development or as a factor that helps maintain neuronal/glial function.

    更新日期:2019-11-01
  • The diverse functions of oxysterol-binding proteins.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2009-07-07
    Sumana Raychaudhuri,William A Prinz

    Oxysterol-binding protein (OSBP)-related proteins (ORPs) are lipid-binding proteins that are conserved from yeast to humans. They are implicated in many cellular processes including signaling, vesicular trafficking, lipid metabolism, and nonvesicular sterol transport. All ORPs contain an OSBP-related domain (ORD) that has a hydrophobic pocket that binds a single sterol. ORDs also contain additional membrane-binding surfaces, some of which bind phosphoinositides and may regulate sterol binding. Studies in yeast suggest that ORPs function as sterol transporters, perhaps in regions where organelle membranes are closely apposed. Yeast ORPs also participate in vesicular trafficking, although their role is unclear. In mammalian cells, some ORPs function as sterol sensors that regulate the assembly of protein complexes in response to changes in cholesterol levels. This review will summarize recent advances in our understanding of how ORPs bind lipids and membranes and how they function in diverse cellular processes.

    更新日期:2019-11-01
  • The epigenetics of rRNA genes: from molecular to chromosome biology.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2008-07-12
    Brian McStay,Ingrid Grummt

    In eukaryotes, the genes encoding ribosomal RNAs (rDNA) exist in two distinct epigenetic states that can be distinguished by a specific chromatin structure that is maintained throughout the cell cycle and is inherited from one cell to another. The fact that even in proliferating cells with a high demand of protein synthesis a fraction of rDNA is silenced provides a unique possibility to decipher the mechanism underlying epigenetic regulation of rDNA. This chapter summarizes our knowledge of the molecular mechanisms that establish and propagate the epigenetic state of rRNA genes, unraveling a complex interplay of DNA methyltransferases and histone-modifying enzymes that act in concert with chromatin remodeling complexes and RNA-guided mechanisms to define the transcriptional state of rDNA. We also review the critical role of the RNA polymerase I transcription factor UBF in the formation of active nucleolar organizer regions (NORs) and maintenance of the euchromatic state of rRNA genes.

    更新日期:2019-11-01
  • Comparative aspects of animal regeneration.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2008-07-05
    Jeremy P Brockes,Anoop Kumar

    Most but not all phyla include examples of species that are able to regenerate large sections of the body plan. The mechanisms underlying regeneration on this scale are currently being studied in a variety of contexts in both vertebrates and invertebrates. Regeneration generally involves the formation of a wound epithelium after transection or injury, followed by the generation of regenerative progenitor cells and morphogenesis to give the regenerate. Common mechanisms may exist in relation to each of these aspects. For example, the initial proliferation of progenitor cells often depends on the nerve supply, whereas morphogenesis reflects the generation of positional disparity between adjacent cells-the principle of intercalation. These mechanisms are reviewed here across a range of contexts. We also consider the evolutionary origins of regeneration and how regeneration may relate to both agametic reproduction and to ontogeny.

    更新日期:2019-11-01
  • Structural and functional aspects of lipid binding by CD1 molecules.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2008-07-03
    Jonathan D Silk,Mariolina Salio,James Brown,E Yvonne Jones,Vincenzo Cerundolo

    Over the past ten years, investigators have shown that T lymphocytes can recognize not only peptides in the context of MHC class I and class II molecules but also foreign and self-lipids in association with the nonclassical MHC class I molecules the CD1 proteins. We describe the events that have led to the discovery of the role of CD1 molecules, their pattern of intracellular trafficking, and their ability to sample different intracellular compartments for self- and foreign lipids. Structural and functional aspects of lipid presentation by CD1 molecules are presented in the context of the function of CD1-restricted T cells in antimicrobial responses, antitumor immunity, and the regulation of the tolerance and autoimmunity immunoregulatory axis. Particular emphasis is on invariant NKT (iNKT) cells and their ability to modulate innate and adaptive immune responses.

    更新日期:2019-11-01
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  • Stress signaling between organs in metazoa.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2015-09-24
    Edward Owusu-Ansah,Norbert Perrimon

    Many organisms have developed a robust ability to adapt and survive in the face of environmental perturbations that threaten the integrity of their genome, proteome, or metabolome. Studies in multiple model organisms have shown that, in general, when exposed to stress, cells activate a complex prosurvival signaling network that includes immune and DNA damage response genes, chaperones, antioxidant enzymes, structural proteins, metabolic enzymes, and noncoding RNAs. The manner of activation runs the gamut from transcriptional induction of genes to increased stability of transcripts to posttranslational modification of important biosynthetic proteins within the stressed tissue. Superimposed on these largely autonomous effects are nonautonomous responses in which the stressed tissue secretes peptides and other factors that stimulate tissues in different organs to embark on processes that ultimately help the organism as a whole cope with stress. This review focuses on the mechanisms by which tissues in one organ adapt to environmental challenges by regulating stress responses in tissues of different organs.

    更新日期:2019-11-01
  • Dscam-mediated cell recognition regulates neural circuit formation.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2008-10-08
    Daisuke Hattori,S Sean Millard,Woj M Wojtowicz,S Lawrence Zipursky

    The Dscam family of immunoglobulin cell surface proteins mediates recognition events between neurons that play an essential role in the establishment of neural circuits. The Drosophila Dscam1 locus encodes tens of thousands of cell surface proteins via alternative splicing. These isoforms exhibit exquisite isoform-specific binding in vitro that mediates homophilic repulsion in vivo. These properties provide the molecular basis for self-avoidance, an essential developmental mechanism that allows axonal and dendritic processes to uniformly cover their synaptic fields. In a mechanistically similar fashion, homophilic repulsion mediated by Drosophila Dscam2 prevents processes from the same class of cells from occupying overlapping synaptic fields through a process called tiling. Genetic studies in the mouse visual system support the view that vertebrate DSCAM also promotes both self-avoidance and tiling. By contrast, DSCAM and DSCAM-L promote layer-specific targeting in the chick visual system, presumably through promoting homophilic adhesion. The fly and mouse studies underscore the importance of homophilic repulsion in regulating neural circuit assembly, whereas the chick studies suggest that DSCAM proteins may mediate a variety of different recognition events during wiring in a context-dependent fashion.

    更新日期:2019-11-01
  • Dorsal-ventral patterning and neural induction in Xenopus embryos.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2004-10-12
    Edward M De Robertis,Hiroki Kuroda

    We review the current status of research in dorsal-ventral (D-V) patterning in vertebrates. Emphasis is placed on recent work on Xenopus, which provides a paradigm for vertebrate development based on a rich heritage of experimental embryology. D-V patterning starts much earlier than previously thought, under the influence of a dorsal nuclear -Catenin signal. At mid-blastula two signaling centers are present on the dorsal side: The prospective neuroectoderm expresses bone morphogenetic protein (BMP) antagonists, and the future dorsal endoderm secretes Nodal-related mesoderm-inducing factors. When dorsal mesoderm is formed at gastrula, a cocktail of growth factor antagonists is secreted by the Spemann organizer and further patterns the embryo. A ventral gastrula signaling center opposes the actions of the dorsal organizer, and another set of secreted antagonists is produced ventrally under the control of BMP4. The early dorsal -Catenin signal inhibits BMP expression at the transcriptional level and promotes expression of secreted BMP antagonists in the prospective central nervous system (CNS). In the absence of mesoderm, expression of Chordin and Noggin in ectoderm is required for anterior CNS formation. FGF (fibroblast growth factor) and IGF (insulin-like growth factor) signals are also potent neural inducers. Neural induction by anti-BMPs such as Chordin requires mitogen-activated protein kinase (MAPK) activation mediated by FGF and IGF. These multiple signals can be integrated at the level of Smad1. Phosphorylation by BMP receptor stimulates Smad1 transcriptional activity, whereas phosphorylation by MAPK has the opposite effect. Neural tissue is formed only at very low levels of activity of BMP-transducing Smads, which require the combination of both low BMP levels and high MAPK signals. Many of the molecular players that regulate D-V patterning via regulation of BMP signaling have been conserved between Drosophila and the vertebrates.

    更新日期:2019-11-01
  • The LIN-12/Notch signaling pathway and its regulation.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 1997-01-01
    J Kimble,P Simpson

    Notch, LIN-12, and GLP-1 are receptors that mediate a broad range of cell interactions during Drosophila and nematode development. Signaling by these receptors relies on a conserved pathway with three core components: DSL ligand, LNG receptor, and a CSL effector that links the receptor to its transcriptional response. Although key functional regions have been identified in each class of proteins, the mechanism for signal transduction is not yet understood. Diverse regulatory mechanisms influence signaling by the LIN-12/Notch pathway. Inductive signaling relies on the synthesis of ligand and receptor in distinct but neighboring cells. By contrast, lateral signaling leads to the transformation of equivalent cells that express both ligand and receptor into nonequivalent cells that express either ligand or receptor. This transformation appears to rely on regulatory feedback loops within the LIN-12/Notch pathway. In addition, the pathway can be regulated by intrinsic factors that are asymmetrically segregated during cell division or by extrinsic cues via other signaling pathways. Specificity in the pathway does not appear to reside in the particular ligand or receptor used for a given cell-cell interaction. The existence of multiple ligands and receptors may have evolved from the stringent demands placed upon the regulation of genes encoding them.

    更新日期:2019-11-01
  • Caspase-dependent cell death in Drosophila.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2006-07-18
    Bruce A Hay,Ming Guo

    Cell death plays many roles during development, in the adult, and in the genesis of many pathological states. Much of this death is apoptotic in nature and requires the activity of members of the caspase family of proteases. It is now possible uniquely in Drosophila to carry out genetic screens for genes that determine the fate-life or death-of any population of cells during development and adulthood. This, in conjunction with the ability to obtain biochemical quantities of material, has made Drosophila a useful organism for exploring the mechanisms by which apoptosis is carried out and regulated. This review summarizes our knowledge of caspase-dependent cell death in Drosophila and compares that knowledge with what is known in worms and mammals. We also discuss the significance of recent work showing that a number of key cell death activators also play nonapoptotic roles. We highlight opportunities and outstanding questions along the way.

    更新日期:2019-11-01
  • Blue-light photoreceptors in higher plants.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 1999-12-28
    W R Briggs,E Huala

    In the past few years great progress has been made in identifying and characterizing plant photoreceptors active in the blue/UV-A regions of the spectrum. These photoreceptors include cryptochrome 1 and cryptochrome 2, which are similar in structure and chromophore composition to the prokaryotic DNA photolyases. However, they have a C-terminal extension that is not present in photolyases and lack photolyase activity. They are involved in regulation of cell elongation and in many other processes, including interfacing with circadian rhythms and activating gene transcription. Animal cryptochromes that play a photoreceptor role in circadian rhythms have also been characterized. Phototropin, the protein product of the NPH1 gene in Arabidopsis, likely serves as the photoreceptor for phototropism and appears to have no other role. A plasma membrane protein, it serves as photoreceptor, kinase, and substrate for light-activated phosphorylation. The carotenoid zeaxanthin may serve as the chromophore for a photoreceptor involved in blue-light-activated stomatal opening. The properties of these photoreceptors and some of the downstream events they are known to activate are discussed.

    更新日期:2019-11-01
  • Light control of plant development.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 1997-01-01
    C Fankhauser,J Chory

    To grow and develop optimally, all organisms need to perceive and process information from both their biotic and abiotic surroundings. A particularly important environmental cue is light, to which organisms respond in many different ways. Because they are photosynthetic and non-motile, plants need to be especially plastic in response to their light environment. The diverse responses of plants to light require sophisticated sensing of its intensity, direction, duration, and wavelength. The action spectra of light responses provided assays to identify three photoreceptor systems absorbing in the red/far-red, blue/near-ultraviolet, and ultraviolet spectral ranges. Following absorption of light, photoreceptors interact with other signal transduction elements, which eventually leads to many molecular and morphological responses. While a complete signal transduction cascade is not known yet, molecular genetic studies using the model plant Arabidopsis have led to substantial progress in dissecting the signal transduction network. Important gains have been made in determining the function of the photoreceptors, the terminal response pathways, and the intervening signal transduction components.

    更新日期:2019-11-01
  • Musashi signaling in stem cells and cancer.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2015-11-14
    Raymond G Fox,Frederick D Park,Claire S Koechlein,Marcie Kritzik,Tannishtha Reya

    How a single cell gives rise to an entire organism is one of biology's greatest mysteries. Within this process, stem cells play a key role by serving as seed cells capable of both self-renewal to sustain themselves as well as differentiation to generate the full diversity of mature cells and functional tissues. Understanding how this balance between self-renewal and differentiation is achieved is crucial to defining not only the underpinnings of normal development but also how its subversion can lead to cancer. Musashi, a family of RNA binding proteins discovered originally in Drosophila and named after the iconic samurai, Miyamoto Musashi, has emerged as a key signal that confers and protects the stem cell state across organisms. Here we explore the role of this signal in stem cells and how its reactivation can be a critical element in oncogenesis. Relative to long-established developmental signals such as Wnt, Hedgehog, and Notch, our understanding of Musashi remains in its infancy; yet all evidence suggests that Musashi will emerge as an equally powerful paradigm for regulating development and cancer and may be destined to have a great impact on biology and medicine.

    更新日期:2019-11-01
  • Regulation of integrin activation.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2011-06-15
    Chungho Kim,Feng Ye,Mark H Ginsberg

    Regulation of cell-cell and cell-matrix interaction is essential for the normal physiology of metazoans and is important in many diseases. Integrin adhesion receptors can rapidly increase their affinity (integrin activation) in response to intracellular signaling events in a process termed inside-out signaling. The transmembrane domains of integrins and their interactions with the membrane are important in inside-out signaling. Moreover, integrin activation is tightly regulated by a complex network of signaling pathways. Here, we review recent progress in understanding how the membrane environment can, in cooperation with integrin-binding proteins, regulate integrin activation.

    更新日期:2019-11-01
  • RNA transport and local control of translation.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2005-10-11
    Stefan Kindler,Huidong Wang,Dietmar Richter,Henri Tiedge

    In eukaryotes, the entwined pathways of RNA transport and local translational regulation are key determinants in the spatio-temporal articulation of gene expression. One of the main advantages of this mechanism over transcriptional control in the nucleus lies in the fact that it endows local sites with independent decision-making authority, a consideration that is of particular relevance in cells with complex cellular architecture such as neurons. Localized RNAs typically contain codes, expressed within cis-acting elements, that specify subcellular targeting. Such codes are recognized by trans-acting factors, adaptors that mediate translocation along cytoskeletal elements by molecular motors. Most transported mRNAs are assumed translationally dormant while en route. In some cell types, especially in neurons, it is considered crucial that translation remains repressed after arrival at the destination site (e.g., a postsynaptic microdomain) until an appropriate activation signal is received. Several candidate mechanisms have been suggested to participate in the local implementation of translational repression and activation, and such mechanisms may target translation at the level of initiation and/or elongation. Recent data indicate that untranslated RNAs may play important roles in the local control of translation.

    更新日期:2019-11-01
  • Regulated cell death: signaling and mechanisms.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2014-08-26
    Avi Ashkenazi,Guy Salvesen

    Cell turnover is a fundamental feature in metazoans. Cells can die passively, as a consequence of severe damage to their structural integrity, or actively, owing to a more confined biological disruption such as DNA damage. Passive cell death is uncontrolled and often harmful to the organism. In contrast, active cell death is tightly regulated and serves to support the organism's life. Apoptosis-the primary form of regulated cell death-is relatively well defined. Necroptosis-an alternative, distinct kind of regulated cell death discovered more recently-is less well understood. Apoptosis and necroptosis can be triggered either from within the cell or by extracellular stimuli. Certain signaling components, including several death ligands and receptors, can regulate both processes. Whereas apoptosis is triggered and executed via intracellular proteases called caspases, necroptosis is suppressed by caspase activity. Here we highlight current understanding of the key signaling mechanisms that control regulated cell death.

    更新日期:2019-11-01
  • The molecular basis of organ formation: insights from the C. elegans foregut.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2008-01-10
    Susan E Mango

    The digestive tracts of many animals are epithelial tubes with specialized compartments to break down food, remove wastes, combat infection, and signal nutrient availability. C. elegans possesses a linear, epithelial gut tube with foregut, midgut, and hindgut sections. The simple anatomy belies the developmental complexity that is involved in forming the gut from a pool of heterogeneous precursor cells. Here, I focus on the processes that specify cell fates and control morphogenesis within the embryonic foregut (pharynx) and the developmental roles of the pharynx after birth. Maternally donated factors in the pregastrula embryo converge on pha-4, a FoxA transcription factor that specifies organ identity for pharyngeal precursors. Positive feedback loops between PHA-4 and other transcription factors ensure commitment to pharyngeal fate. Binding-site affinity of PHA-4 for its target promoters contributes to the progression of the pharyngeal precursors towards differentiation. During morphogenesis, the pharyngeal precursors form an epithelial tube in a process that is independent of cadherins, catenins, and integrins but requires the kinesin zen-4/MKLP1. After birth, the pharynx and/or pha-4 are involved in repelling pathogens and controlling aging.

    更新日期:2019-11-01
  • Vertebrate endoderm development and organ formation.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2009-07-07
    Aaron M Zorn,James M Wells

    The endoderm germ layer contributes to the respiratory and gastrointestinal tracts and to all of their associated organs. Over the past decade, studies in vertebrate model organisms, including frog, fish, chick, and mouse, have greatly enhanced our understanding of the molecular basis of endoderm organ development. We review this progress with a focus on early stages of endoderm organogenesis including endoderm formation, gut tube morphogenesis and patterning, and organ specification. Lastly, we discuss how developmental mechanisms that regulate endoderm organogenesis are used to direct differentiation of embryonic stem cells into specific adult cell types, which function to alleviate disease symptoms in animal models.

    更新日期:2019-11-01
  • Plasma membrane disruption: repair, prevention, adaptation.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Paul L McNeil,Richard A Steinhardt

    Many metazoan cells inhabit mechanically stressful environments and, consequently, their plasma membranes are frequently disrupted. Survival requires that the cell rapidly repair or reseal the disruption. Rapid resealing is an active and complex structural modification that employs endomembrane as its primary building block, and cytoskeletal and membrane fusion proteins as its catalysts. Endomembrane is delivered to the damaged plasma membrane through exocytosis, a ubiquitous Ca2+-triggered response to disruption. Tissue and cell level architecture prevent disruptions from occurring, either by shielding cells from damaging levels of force, or, when this is not possible, by promoting safe force transmission through the plasma membrane via protein-based cables and linkages. Prevention of disruption also can be a dynamic cell or tissue level adaptation triggered when a damaging level of mechanical stress is imposed. Disease results from failure of either the preventive or resealing mechanisms.

    更新日期:2019-11-01
  • Adhesion-dependent cell mechanosensitivity.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Alexander D Bershadsky,Nathalie Q Balaban,Benjamin Geiger

    The conversion of physical signals, such as contractile forces or external mechanical perturbations, into chemical signaling events is a fundamental cellular process that occurs at cell-extracellular matrix contacts, known as focal adhesions. At these sites, transmembrane integrin receptors are associated via their cytoplasmic domains with the actin cytoskeleton. This interaction with actin is mediated by a submembrane plaque, consisting of numerous cytoskeletal and signaling molecules. Application of intrinsic or external forces to these structures dramatically affects their assembly and triggers adhesion-mediated signaling. In this review, we discuss the structure-function relationships of focal adhesions and the possible mode of action of the putative mechanosensor associated with them. We also discuss the general phenomenon of mechanosensitivity, and the approaches used to measure local forces at adhesion sites, the cytoskeleton-mediated regulation of local contractility, and the nature of the signaling networks that both affect contractility and are affected by it.

    更新日期:2019-11-01
  • Quality control and protein folding in the secretory pathway.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    E Sergio Trombetta,Armando J Parodi

    The biosynthesis of secretory and membrane proteins in the endoplasmic reticulum (ER) yields mostly properly folded and assembled structures with full biological activity. Such fidelity is maintained by quality control (QC) mechanisms that avoid the production of nonnative structures. QC relies on chaperone systems in the ER that monitor and assist in the folding process. When folding promotion is not sufficient, proteins are retained in the ER and eventually retranslocated to the cytosol for degradation by the ubiquitin proteasome pathway. Retention of proteins that fail QC can sometimes occur beyond the ER, and degradation can take place in lysosomes. Several diseases are associated with proteins that do not pass QC, fail to be degraded efficiently, and accumulate as aggregates. In other cases, pathology arises from the downregulation of mutated but potentially functional proteins that are retained and degraded by the QC system.

    更新日期:2019-11-01
  • Branching morphogenesis of the Drosophila tracheal system.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Amin Ghabrial,Stefan Luschnig,Mark M Metzstein,Mark A Krasnow

    Many organs including the mammalian lung and vascular system consist of branched tubular networks that transport essential gases or fluids, but the genetic programs that control the development of these complex three-dimensional structures are not well understood. The Drosophila melanogaster tracheal (respiratory) system is a network of interconnected epithelial tubes that transports oxygen and other gases in the body and provides a paradigm of branching morphogenesis. It develops by sequential sprouting of primary, secondary, and terminal branches from an epithelial sac of approximately 80 cells in each body segment of the embryo. Mapping of the cell movements and shape changes during the sprouting process has revealed that distinct mechanisms of epithelial migration and tube formation are used at each stage of branching. Genetic dissection of the process has identified a general program in which a fibroblast growth factor (FGF) and fibroblast growth factor receptor (FGFR) are used repeatedly to control branch budding and outgrowth. At each stage of branching, the mechanisms controlling FGF expression and the downstream signal transduction pathway change, altering the pattern and structure of the branches that form. During terminal branching, FGF expression is regulated by hypoxia, ensuring that tracheal structure matches cellular oxygen need. A branch diversification program operates in parallel to the general budding program: Regional signals locally modify the general program, conferring specific structural features and other properties on individual branches, such as their substrate outgrowth preferences, differences in tube size and shape, and the ability to fuse to other branches to interconnect the network.

    更新日期:2019-11-01
  • Nodal signaling in vertebrate development.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Alexander F Schier

    TGFss signals belonging to the Nodal family set up the embryonic axes, induce mesoderm and endoderm, pattern the nervous system, and determine left-right asymmetry in vertebrates. Nodal signaling activates a canonical TGFss pathway involving activin receptors, Smad2 transcription factors, and FoxH1 coactivators. In addition, Nodal signaling is dependent on coreceptors of the EGF-CFC family and antagonized by the Lefty and Cerberus families of secreted factors. Additional modulators of Nodal signaling include convertases that regulate the generation of the mature signal, and factors such as Arkadia and DRAP1 that regulate the cellular responses to the signal. Complex regulatory cascades and autoregulatory loops coordinate Nodal signaling during early development. Nodals have concentration-dependent roles and can act both locally and at a distance. These studies demonstrate that Nodal signaling is modulated at almost every level to precisely orchestrate tissue patterning during vertebrate embryogenesis.

    更新日期:2019-11-01
  • Proteolysis in bacterial regulatory circuits.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Susan Gottesman

    Proteolysis by cytoplasmic, energy-dependent proteases plays a critical role in many regulatory circuits, keeping basal levels of regulatory proteins low and rapidly removing proteins when they are no longer needed. In bacteria, four families of energy-dependent proteases carry out degradation. In all of them, substrates are first recognized and bound by ATPase domains and then unfolded and translocated to a sequestered proteolytic chamber. Substrate selection depends not on ubiquitin but on intrinsic recognition signals within the proteins and, in some cases, on adaptor or effector proteins that participate in delivering the substrate to the protease. For some, the activity of these adaptors can be regulated, which results in regulated proteolysis. Recognition motifs for proteolysis are frequently found at the N and C termini of substrates. Proteolytic switches appear to be critical for cell cycle development in Caulobacter crescentus, for proper sporulation in Bacillus subtilis, and for the transition in and out of stationary phase in Escherichia coli. In eukaryotes, the same proteases are found in organelles, where they also play important roles.

    更新日期:2019-11-01
  • Ena/VASP proteins: regulators of the actin cytoskeleton and cell migration.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Matthias Krause,Erik W Dent,James E Bear,Joseph J Loureiro,Frank B Gertler

    Ena/VASP proteins are a conserved family of actin regulatory proteins made up of EVH1, EVH2 domains, and a proline-rich central region. They have been implicated in actin-based processes such as fibroblast migration, axon guidance, and T cell polarization and are important for the actin-based motility of the intracellular pathogen Listeria monocytogenes. Mechanistically, these proteins associate with barbed ends of actin filaments and antagonize filament capping by capping protein (CapZ). In addition, they reduce the density of Arp2/3-dependent actin filament branches and bind Profilin at sites of actin polymerization. Vertebrate Ena/VASP proteins are substrates for PKA/PKG serine/threonine kinases. Phosphorylation by these kinases appears to modulate Ena/VASP function within cells, although the mechanism underlying this regulation remains to be determined.

    更新日期:2019-11-01
  • Structure, function, and regulation of budding yeast kinetochores.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Andrew D McAinsh,Jessica D Tytell,Peter K Sorger

    Kinetochores are multiprotein complexes that assemble on centromeric DNA and mediate the attachment and movement of chromosomes along the microtubules (MTs) of the mitotic spindle. This review focuses on the simplest eukaryotic centromeres and kinetochores, those found in the budding yeast Saccharomyces cerevisiae. Research on kinetochore function and chromosome segregation is focused on four questions of general significance: what specifies the location of centromeres? What are the protein components of kinetochores, and how do they assemble a MT attachment site? How do MT attachments generate force? How do cells sense the state of attachment via the spindle assembly checkpoint?

    更新日期:2019-11-01
  • SNARE protein structure and function.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Daniel Ungar,Frederick M Hughson

    The SNARE superfamily has become, since its discovery approximately a decade ago, the most intensively studied element of the protein machinery involved in intracellular trafficking. Intracellular membrane fusion in eukaryotes requires SNARE (soluble N-ethylmaleimide-sensitive-factor attachment protein receptor) proteins that form complexes bridging the two membranes. Although common themes have emerged from structural and functional studies of SNAREs and other components of the eukaryotic membrane fusion machinery, there is still much to learn about how the assembly and activity of this machinery is choreographed in living cells.

    更新日期:2019-11-01
  • Pigment cells: a model for the study of organelle transport.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Alexandra A Nascimento,Joseph T Roland,Vladimir I Gelfand

    Eukaryotic organisms rely on intracellular transport to position organelles and other components within their cells. Pigment cells provide an excellent model to study organelle transport as they specialize in the translocation of pigment granules in response to defined chemical signals. Pigment cells of lower vertebrates have traditionally been used as a model for these studies because these cells transport pigment organelles in a highly coordinated fashion, are easily cultured and transfected, are ideal for microsurgery, and are good for biochemical experiments, including in vitro analysis of organelle motility. Many important properties of organelle transport, for example, the requirement of two cytoskeletal filaments (actin and microtubules), the motor proteins involved, and the mechanisms of their regulation and interactions, have been studied using pigment cells of lower vertebrates. Genetic studies of mouse melanocytes allowed the discovery of essential elements involved in organelle transport including the myosin-Va motor and its receptor and adaptor molecules on the organelle surface. Future studies of pigment cells will contribute to our understanding of issues such as the cooperation among multiple motor proteins and the mechanisms of regulation of microtubule motors.

    更新日期:2019-11-01
  • The dynamic and motile properties of intermediate filaments.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Brian T Helfand,Lynne Chang,Robert D Goldman

    For many years, cytoplasmic intermediate filaments (IFs) were considered to be stable cytoskeletal elements contributing primarily to the maintenance of the structural and mechanical integrity of cells. However, recent studies of living cells have revealed that IFs and their precursors possess a remarkably wide array of dynamic and motile properties. These properties are in large part due to interactions with molecular motors such as conventional kinesin, cytoplasmic dynein, and myosin. The association between IFs and motors appears to account for much of the well-documented molecular cross talk between IFs and the other major cytoskeletal elements, microtubules, and actin-containing microfilaments. Furthermore, the associations with molecular motors are also responsible for the high-speed, targeted delivery of nonfilamentous IF protein cargo to specific regions of the cytoplasm where they polymerize into IFs. This review considers the functional implications of the motile properties of IFs and discusses the potential relationships between malfunctions in these motile activities and human diseases.

    更新日期:2019-11-01
  • Intraflagellar transport.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Jonathan M Scholey

    It has been a decade since a novel form of microtubule (MT)-based motility, i.e., intraflagellar transport (IFT), was discovered in Chlamydomonas flagella. Subsequent research has supported the hypothesis that IFT is required for the assembly and maintenance of all cilia and flagella and that its underlying mechanism involves the transport of nonmembrane-bound macromolecular protein complexes (IFT particles) along axonemal MTs beneath the ciliary membrane. IFT requires the action of the anterograde kinesin-II motors and the retrograde IFT-dynein motors to transport IFT particles in opposite directions along the MT polymer lattice from the basal body to the tip of the axoneme and back again. A rich diversity of biological processes has been shown to depend upon IFT, including flagellar length control, cell swimming, mating and feeding, photoreception, animal development, sensory perception, chemosensory behavior, and lifespan control. These processes reflect the varied roles of cilia and flagella in motility and sensory signaling.

    更新日期:2019-11-01
  • Tetraspanin proteins mediate cellular penetration, invasion, and fusion events and define a novel type of membrane microdomain.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Martin E Hemler

    This review summarizes key aspects of tetraspanin proteins, with a focus on the functional relevance and structural features of these proteins and how they are organized into a novel type of membrane microdomain. Despite the size of the tetraspanin family and their abundance and wide distribution over many cell types, most have not been studied. However, from studies of prototype tetraspanins, information regarding functions, cell biology, and structural organization has begun to emerge. Genetic evidence points to critical roles for tetraspanins on oocytes during fertilization, in fungi during leaf invasion, in Drosophila embryos during neuromuscular synapse formation, during T and B lymphocyte activation, in brain function, and in retinal degeneration. From structure and mutagenesis studies, we are beginning to understand functional subregions within tetraspanins, as well as the levels of connections among tetraspanins and their many associated proteins. Tetraspanin-enriched microdomains (TEMs) are emerging as entities physically and functionally distinct from lipid rafts. These microdomains now provide a context in which to evaluate tetraspanins in the regulation of growth factor signaling and in the modulation of integrin-mediated post-cell adhesion events. Finally, the enrichment of tetraspanins within secreted vesicles called exosomes, coupled with hints that tetraspanins may regulate vesicle fusion and/or fission, suggests exciting new directions for future research.

    更新日期:2019-11-01
  • Modulation of notch signaling during somitogenesis.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Gerry Weinmaster,Chris Kintner

    The Notch signaling pathway is known to govern various aspects of tissue differentiation during embryonic development by mediating local cell-cell interactions that often control cell fate. The conserved components that underlie Notch signaling have been isolated in vertebrates, leading to a biochemical delineation of a core Notch signaling pathway and functional studies of this pathway during embryogenesis. Herein we highlight recent progress in determining how Notch signaling contributes to the development of the vertebrate embryo. We first discuss the role of Notch in the process of segmentation where rapid changes have been shown to occur in both the spatial and temporal aspects of Notch signaling, which are critical for segmental patterning. Indeed, the role of Notch in segmentation re-emphasizes a recurring question in Notch biology: how are the components involved in Notch signaling regulated to ensure their dynamic properties? Second, we address this question by discussing recent work on the biochemical mechanisms that potentially regulate Notch signaling during segmentation, including those that act on the receptors, ligands, and signal transduction apparatus.

    更新日期:2019-11-01
  • Transport protein trafficking in polarized cells.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Theodore R Muth,Michael J Caplan

    In order to carry out their physiological functions, ion transport proteins must be targeted to the appropriate domains of cell membranes. Regulation of ion transport activity frequently involves the tightly controlled delivery of intracellular populations of transport proteins to the plasma membrane or the endocytic retrieval of transport proteins from the cell surface. Transport proteins carry signals embedded within their structures that specify their subcellular distributions and endow them with the capacity to participate in regulated membrane trafficking processes. Recently, a great deal has been learned about the biochemical nature of these signals, as well as about the cellular machinery that interprets them and acts upon their messages.

    更新日期:2019-11-01
  • Actin assembly and endocytosis: from yeast to mammals.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Asa E Y Engqvist-Goldstein,David G Drubin

    Internalization of receptors, lipids, pathogens, and other cargo at the plasma membrane involves several different pathways and requires coordinated interactions between a variety of protein and lipid molecules. The actin cytoskeleton is an integral part of the cell cortex, and there is growing evidence that F-actin plays a direct role in these endocytic events. Genetic studies in yeast have firmly established a functional connection between actin and endocytosis. Identification of several proteins that may function at the interface between actin and the endocytic machinery has provided further evidence for this association in both yeast and mammalian cells. Several of these proteins are directly involved in regulating actin assembly and could thus harness forces produced during actin polymerization to facilitate specific steps in the endocytic process. Recent microscopy studies in mammalian cells provide powerful evidence that localized recruitment and polymerization of actin occurs at endocytic sites. In this review, we focus on progress made in elucidating the functions of the actin cytoskeleton in endocytosis.

    更新日期:2019-11-01
  • The COP9 signalosome.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Ning Wei,Xing Wang Deng

    The COP9 signalosome (CSN) is composed of eight distinct subunits and is highly homologous to the lid sub-complex of the 26S proteasome. CSN was initially defined as a repressor of photomorphogenesis in Arabidopsis, and it has now been found to participate in diverse cellular and developmental processes in various eukaryotic organisms. Recently, CSN was revealed to have a metalloprotease activity centered in the CSN5/Jab1 subunit, which removes the post-translational modification of a ubiquitin-like protein, Nedd8/Rub1, from the cullin component of SCF ubiquitin E3 ligase (i.e., de-neddylation). In addition, CSN is associated with de-ubiquitination activity and protein kinase activities capable of phosphorylating important signaling regulators. The involvement of CSN in a number of cellular and developmental processes has been attributed to its control over ubiquitin-proteasome-mediated protein degradation.

    更新日期:2019-11-01
  • Genomic imprinting: intricacies of epigenetic regulation in clusters.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Raluca I Verona,Mellissa R W Mann,Marisa S Bartolomei

    An intriguing characteristic of imprinted genes is that they often cluster in large chromosomal domains, raising the possibility that gene-specific and domain-specific mechanisms regulate imprinting. Several common features emerged from comparative analysis of four imprinted domains in mice and humans: (a) Certain genes appear to be imprinted by secondary events, possibly indicating a lack of gene-specific imprinting marks; (b) some genes appear to resist silencing, predicting the presence of cis-elements that oppose domain-specific imprinting control; (c) the nature of the imprinting mark remains incompletely understood. In addition, common silencing mechanisms are employed by the various imprinting domains, including silencer elements that nucleate and propagate a silent chromatin state, insulator elements that prevent promoter-enhancer interactions when hypomethylated on one parental allele, and antisense RNAs that function in silencing the overlapping sense gene and more distantly located genes. These commonalities are reminiscent of the behavior of genes subjected to, and the mechanisms employed in, dosage compensation.

    更新日期:2019-11-01
  • Cadherins as modulators of cellular phenotype.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Margaret J Wheelock,Keith R Johnson

    Cadherins are transmembrane glycoproteins that mediate calcium-dependent cell-cell adhesion. The cadherin family is large and diverse, and proteins are considered to be members of this family if they have one or more cadherin repeats in their extracellular domain. Cadherin family members are the transmembrane components of a number of cellular junctions, including adherens junctions, desmosomes, cardiac junctions, endothelial junctions, and synaptic junctions. Cadherin function is critical in normal development, and alterations in cadherin function have been implicated in tumorigenesis. The strength of cadherin interactions can be regulated by a number of proteins, including the catenins, which serve to link the cadherin to the cytoskeleton. Cadherins have been implicated in a number of signaling pathways that regulate cellular behavior, and it is becoming increasingly clear that integration of information received from cell-cell signaling, cell-matrix signaling, and growth factor signaling determines ultimate cellular phenotype and behavior.

    更新日期:2019-11-01
  • Positional control of cell fate through joint integrin/receptor protein kinase signaling.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Filippo G Giancotti,Guido Tarone

    Cells adhere to the extracellular matrix throughout most of their lifetime. This close, intimate contact with the matrix exerts an extraordinary control on the behavior of cells, determining whether they move or stay put, proliferate or remain quiescent, and even live or die. Attachment to the matrix not only enables cells to respond to soluble growth factors and cytokines but also determines the nature of the response. The integrins are a large family of receptors that attach cells to the matrix, organize their cytoskeleton, and cooperate with receptor protein tyrosine kinases to regulate cell fate. Research on integrin signaling is beginning to explain the complex and specific effects that the extracellular matrix exerts on cells.

    更新日期:2019-11-01
  • Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Linda Hicke,Rebecca Dunn

    Ubiquitin regulates protein transport between membrane compartments by serving as a sorting signal on protein cargo and by controlling the activity of trafficking machinery. Monoubiquitin attached to integral plasma membrane proteins or to associated transport modifiers serves as a regulated signal for internalization into the endocytic pathway. Similarly, monoubiquitin attached to biosynthetic and endocytic membrane proteins is a signal for sorting of cargo into vesicles that bud into the late endosome lumen for delivery into the lysosome. Ubiquitination of trans-acting endocytic proteins is also required for transport, and key endocytic proteins are modified by monoubiquitin. Regulatory enzymes of the ubiquitination machinery, ubiquitin ligases, control the timing and specificity of plasma membrane protein downregulation in such diverse biological processes as cell fate specification and neurotransmission. Monoubiquitin signals appended by these ligases are recognized by endocytic proteins carrying ubiquitin-binding motifs, including UBA, UEV, UIM, and CUE domains. The UIM proteins epsins and Hrs are excellent candidates for adaptors that link ubiquitinated cargo to the clathrin-based sorting machinery at appropriate regions of the endosomal or plasma membranes. Other ubiquitin-binding proteins also play crucial roles in cargo transport, although in most cases the role of ubiquitin-binding is not defined. Ubiquitin-binding proteins such as epsins, Hrs, and Vps9 are monoubiquitinated, indicating the general nature of ubiquitin regulation in endocytosis and suggesting new models to explain how recognition of monoubiquitin signals may be regulated.

    更新日期:2019-11-01
  • Flower development: initiation, differentiation, and diversification.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Moriyah Zik,Vivian F Irish

    Flowering is one of the most intensively studied processes in plant development. Despite the wide diversity in floral forms, flowers have a simple stereotypical architecture. Flowers develop from florally determined meristems. These small populations of cells proliferate to form the floral organs, including the sterile outer organs, the sepals and petals, and the inner reproductive organs, the stamens and carpels. In the past decade, analyses of key flowering genes have been carried out primarily in Arabidopsis and have provided a foundation for understanding the underlying molecular genetic mechanisms controlling different aspects of floral development. Such studies have illuminated the transcriptional cascades responsible for the regulation of these key genes, as well as how these genes effect their functions. In turn, these studies have resulted in the refinement of the original ideas of how flowers develop and have indicated the gaps in our knowledge that need to be addressed.

    更新日期:2019-11-01
  • Regulation of MAP kinase signaling modules by scaffold proteins in mammals.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Deborah K Morrison,Roger J Davis

    The mitogen-activated protein kinase (MAPK) group of serine/threonine protein kinases mediates the response of cells to many extracellular stimuli such as cytokines and growth factors. These protein kinases include the extracellular signal-regulated protein kinases (ERK) and two stress-activated protein kinases (SAPK), the c-Jun N-terminal kinases (JNK), and the p38 MAPK. The enzymes are evolutionarily conserved and are activated by a common mechanism that involves a protein kinase cascade. Scaffold proteins have been proposed to interact with MAPK pathway components to create a functional signaling module and to control the specificity of signal transduction. Here we critically evaluate the evidence that supports a physiologically relevant role of MAPK scaffold proteins in mammals.

    更新日期:2019-11-01
  • Genes, signals, and lineages in pancreas development.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    L Charles Murtaugh,Douglas A Melton

    Type I diabetes results from the autoimmune-mediated destruction of pancreatic beta cells, which regulate blood sugar levels by secretion of insulin. Recent clinical data suggest that the disease could be cured if an adequate supply of new beta-cells were available, and one goal of pancreatic developmental biology is to understand how endogenous beta-cells are made, with the hope of making them exogenously. Much is now known about the transcriptional regulation of pancreatic organ specification, growth, and lineage allocation; less is known about intercellular signals that regulate this process, but candidates continue to emerge. Additional insights, often contradicting older models, have come from the application of new lineage-tracing techniques. Altogether, these studies also shed light on the still-elusive pancreatic stem cell, which may participate in normal organ maintenance as well as recovery from injury. A rigorous proof of the existence of such a cell, whether in vivo or in vitro, would offer real hope for the prospect of controlled beta-cell generation in a clinical setting.

    更新日期:2019-11-01
  • Anthrax toxin.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    R John Collier,John A T Young

    Anthrax toxin consists of three nontoxic proteins that associate in binary or ternary combinations to form toxic complexes at the surface of mammalian cells. One of these proteins, protective antigen (PA), transports the other two, edema factor (EF) and lethal factor (LF), to the cytosol. LF is a Zn2+-protease that cleaves certain MAP kinase kinases, leading to death of the host via a poorly defined sequence of events. EF, a calmodulin- and Ca2+-dependent adenylate cyclase, is responsible for the edema seen in the disease. Both enzymes are believed to benefit the bacteria by inhibiting cells of the host's innate immune system. Assembly of toxic complexes begins after PA binds to cellular receptors and is cleaved into two fragments by furin proteases. The smaller fragment dissociates, allowing the receptor-bound fragment, PA63 (63 kDa), to self-associate and form a ring-shaped, heptameric pore precursor (prepore). The prepore binds up to three molecules of EF and/or LF, and the resulting complexes are endocytosed and trafficked to an acidic compartment. There, the prepore converts to a transmembrane pore, mediating translocation of EF and LF to the cytosol. Recent studies have revealed (a) the identity of receptors; (b) crystallographic structures of the three toxin proteins and the heptameric PA63 prepore; and (c) information about toxin assembly, entry, and action within the cytosol. Knowledge of the structure and mode of action of the toxin has unveiled potential applications in medicine, including approaches to treating anthrax infections.

    更新日期:2019-11-01
  • Cyclic nucleotide-gated ion channels.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Kimberly Matulef,William N Zagotta

    Cyclic nucleotide-gated (CNG) ion channels were first discovered in rod photoreceptors, where they are responsible for the primary electrical signal of the photoreceptor in response to light. CNG channels are highly specialized membrane proteins that open an ion-permeable pore across the membrane in response to the direct binding of intracellular cyclic nucleotides. CNG channels have been identified in a number of other tissues, including the brain, where their roles are only beginning to be appreciated. Recently, significant progress has been made in understanding the molecular mechanisms underlying their functional specializations. From these studies, a picture is beginning to emerge for how the binding of cyclic nucleotide is transduced into the opening of the pore and how this allosteric transition is modulated by various physiological effectors.

    更新日期:2019-11-01
  • Adult stem cell plasticity: fact or artifact?
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2003-10-23
    Martin Raff

    There has been unprecedented recent interest in stem cells, mainly because of the hope they offer for cell therapy. Adult stem cells are an attractive source of cells for therapy, especially in view of the recent claims that they are remarkably plastic in their developmental potential when exposed to new environments. Some of these claims have been either difficult to reproduce or shown to be misinterpretations, leaving the phenomenon of adult stem cell plasticity under a cloud. There are, however, other examples of plasticity where differentiated cells or their precursors can be reprogrammed by extracellular cues to alter their character in ways that could have important implications for cell therapy and other forms of regenerative treatment.

    更新日期:2019-11-01
  • Remembrance of things past: chromatin remodeling in plant development.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2002-07-27
    Justin Goodrich,Susan Tweedie

    Chromatin remodeling in plants has usually been discussed in relation to aspects of genome defense such as transgene silencing and the resetting of transposon activity. The role of remodeling in controlling development has been less emphasized, although well established in animal systems. This is because cell fate in plants is often held to be entirely specified on the basis of position, apparently excluding any significant role for cell ancestry and chromatin remodeling. We argue that chromatin remodeling is used to confer mitotically heritable cell fates at late stages in pattern formation. Several examples in which chromatin remodeling factors are used to confer a memory of transient events in plant development are discussed. Because the precise biochemical functions of most remodeling factors are obscure, and little is known of plant chromatin structure, the underlying mechanisms remain poorly understood.

    更新日期:2019-11-01
  • Cellular control of actin nucleation.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2002-07-27
    Matthew D Welch,R Dyche Mullins

    Eukaryotic cells use actin polymerization to change shape, move, and internalize extracellular materials by phagocytosis and endocytosis, and to form contractile structures. In addition, several pathogens have evolved to use host cell actin assembly for attachment, internalization, and cell-to-cell spread. Although cells possess multiple mechanisms for initiating actin polymerization, attention in the past five years has focused on the regulation of actin nucleation-the formation of new actin filaments from actin monomers. The Arp2/3 complex and the multiple nucleation-promoting factors (NPFs) that regulate its activity comprise the only known cellular actin-nucleating factors and may represent a universal machine, conserved across eukaryotic phyla, that nucleates new actin filaments for various cellular structures with numerous functions. This review focuses on our current understanding of the mechanism of actin nucleation by the Arp2/3 complex and NPFs and how these factors work with other cytoskeletal proteins to generate structurally and functionally diverse actin arrays in cells.

    更新日期:2019-11-01
  • Membrane fusion in eukaryotic cells.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2002-07-27
    Andreas Mayer

    Membrane fusion is a fundamental biochemical reaction and the final step in all vesicular trafficking events. It is crucial for the transfer of proteins and lipids between different compartments and for exo- and endocytic traffic of signaling molecules and receptors. It leads to the reconstruction of organelles such as the Golgi or the nuclear envelope, which decay into fragments during mitosis. Hence, controlled membrane fusion reactions are indispensible for the compartmental organization of eukaryotic cells; for their communication with the environment via hormones, neurotransmitters, growth factors, and receptors; and for the integration of cells into multicellular organisms. Intracellular pathogenic bacteria, such as Mycobacteria or Salmonellae, have developed means to control fusion reactions in their host cells. They persist in phagosomes whose fusion with lysosomes they actively suppress-a means to ensure survival inside host cells. The past decade has witnessed rapid progress in the elucidation of parts of the molecular machinery involved in these membrane fusion reactions. Whereas some elements of the fusion apparatus are remarkably similar in several compartments, there is an equally striking divergence of others. The purpose of this review is to highlight common features of different fusion reactions and the concepts that emerged from them but also to stress the differences and challenge parts of the current hypotheses. This review covers only the endoplasmic fusion reactions mentioned above, i.e., reactions initiated by contacts of membranes with their cytoplasmic faces. Ectoplasmic fusion events, which depend on an initial contact of the fusion partners via the membrane surfaces exposed to the surrounding medium are not discussed, nor are topics such as the entry of enveloped viruses, formation of syncytia, gamete fusion, or vesicle scission (a fusion reaction that leads to the fission of, e.g., transport vesicles).

    更新日期:2019-11-01
  • Chromosome-microtubule interactions during mitosis.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2002-07-27
    J Richard McIntosh,Ekaterina L Grishchuk,Robert R West

    Spindle microtubules interact with mitotic chromosomes, binding to their kinetochores to generate forces that are important for accurate chromosome segregation. Motor enzymes localized both at kinetochores and spindle poles help to form the biologically significant attachments between spindle fibers and their cargo, but microtubule-associated proteins without motor activity contribute to these junctions in important ways. This review examines the molecules necessary for chromosome-microtubule interaction in a range of well-studied organisms, using biological diversity to identify the factors that are essential for organized chromosome movement. We conclude that microtubule dynamics and the proteins that control them are likely to be more important for mitosis than the current enthusiasm for motor enzymes would suggest.

    更新日期:2019-11-01
  • Proteolysis and sterol regulation.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2002-07-27
    Randolph Y Hampton

    The mammalian cell continuously adjusts its sterol content by regulating levels of key sterol synthetic enzymes and levels of LDL receptors that mediate uptake of cholesterol-laden particles. Control is brought about by sterol-regulated transcription of relevant genes and by regulated degradation of the committed step enzyme HMG-CoA reductase (HMGR). Current work has revealed that proteolysis is at the heart of each of these mechanistically distinct axes. Transcriptional control is effected by regulated cleavage of the membrane-bound transcription factor sterol regulatory element binding protein (SREBP), and HMGR degradation is brought about by ubiquitin-mediated degradation. In each case, ongoing cell biological processes are being harnessed to bring about regulation. The secretory pathway plays a central role in allowing sterol-mediated control of transcription. The constitutively active endoplasmic reticulum (ER) quality control apparatus is employed to bring about regulated destruction of HMGR. This review describes the methods and results of various studies to understand the mechanisms and molecules involved in these distinct but interrelated aspects of sterol regulation and the intriguing similarities that appear to exist at the levels of protein sequence and cell biology.

    更新日期:2019-11-01
  • Actin cytoskeleton regulation in neuronal morphogenesis and structural plasticity.
    Annu. Rev. Cell Dev. Biol. (IF 10.833) Pub Date : 2002-07-27
    Liqun Luo

    The actin cytoskeleton plays a major role in morphological development of neurons and in structural changes of adult neurons. This article reviews the myriad functions of actin and myosin in axon initiation, growth, guidance and branching, in morphogenesis of dendrites and dendritic spines, in synapse formation and stability, and in axon and dendrite retraction. Evidence is presented that signaling pathways involving the Rho family of small GTPases are key regulators of actin polymerization and myosin function in the context of different aspects of neuronal morphogenesis. These studies support an emerging theme: Different aspects of neuronal morphogenesis may involve regulation of common core signaling pathways, in particular the Rho GTPases.

    更新日期:2019-11-01
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