Showing papers in "Annual Review of Cell and Developmental Biology in 1999"

Biochemical Pathways of Caspase Activation During Apoptosis

Abstract: ▪ Abstract Caspase activation plays a central role in the execution of apoptosis. The key components of the biochemical pathways of caspase activation have been recently elucidated. In this review, we focus on the two most well-studied pathways of caspase activation: the cell surface death receptor pathway and the mitochondria-initiated pathway. In the cell surface death receptor pathway, activation of caspase-8 following its recruitment to the death-inducing signaling complex (DISC) is the critical event that transmits the death signal. This event is regulated at several different levels by various viral and mammalian proteins. Activated caspase-8 can activate downstream caspases by direct cleavage or indirectly by cleaving Bid and inducing cytochrome c release from the mitochondria. In the mitochondrial-initiated pathway, caspase activation is triggered by the formation of a multimeric Apaf-1/cytochrome c complex that is fully functional in recruiting and activating procaspase-9. Activated caspase-9 wil...

Transport between the cell nucleus and the cytoplasm.

Abstract: ▪ Abstract The compartmentation of eukaryotic cells requires all nuclear proteins to be imported from the cytoplasm, whereas, for example, transfer RNAs, messenger RNAs, and ribosomes are made in the nucleus and need to be exported to the cytoplasm. Nuclear import and export proceed through nuclear pore complexes and can occur along a great number of distinct pathways, many of which are mediated by importin β-related nuclear transport receptors. These receptors shuttle between nucleus and cytoplasm, and they bind transport substrates either directly or via adapter molecules. They all cooperate with the RanGTPase system to regulate the interactions with their cargoes. Another focus of our review is nuclear export of messenger RNA, which apparently largely relies on export mediators distinct from importin β-related factors. We discuss mechanistic aspects and the energetics of transport receptor function and describe a number of pathways in detail.

Regulation of mammalian o2 homeostasis by hypoxia-inducible factor 1

Abstract: Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic-helix-loop-helix-PAS transcription factor consisting of HIF-1 alpha and HIF-1 beta subunits. HIF-1 alpha expression and HIF-1 transcriptional activity increase exponentially as cellular O2 concentration is decreased. Several dozen target genes that are transactivated by HIF-1 have been identified, including those encoding erythropoietin, glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. The products of these genes either increase O2 delivery or allow metabolic adaptation to reduced O2 availability. HIF-1 is required for cardiac and vascular development and embryonic survival. In fetal and postnatal life, HIF-1 is required for a variety of physiological responses to chronic hypoxia. HIF-1 expression is increased in tumor cells by multiple mechanisms and may mediate adaptation to hypoxia that is critical for tumor progression. HIF-1 thus appears to function as a master regulator of O2 homeostasis that plays essential roles in cellular and systemic physiology, development, and pathophysiology.

SCF and Cullin/RING H2-Based Ubiquitin Ligases

Abstract: Protein degradation is deployed to modulate the steady-state abundance of proteins and to switch cellular regulatory circuits from one state to another by abrupt elimination of control proteins. In eukaryotes, the bulk of the protein degradation that occurs in the cytoplasm and nucleus is carried out by the 26S proteasome. In turn, most proteins are thought to be targeted to the 26S proteasome by covalent attachment of a multiubiquitin chain. Ubiquitination of proteins requires a multienzyme system. A key component of ubiquitination pathways, the ubiquitin ligase, controls both the specificity and timing of substrate ubiquitination. This review is focused on a conserved ubiquitin ligase complex known as SCF that plays a key role in marking a variety of regulatory proteins for destruction by the 26S proteasome.

Proteins of the ADF/Cofilin Family: Essential Regulators of Actin Dynamics

Abstract: Ubiquitous among eukaryotes, the ADF/cofilins are essential proteins responsible for the high turnover rates of actin filaments in vivo. In vertebrates, ADF and cofilin are products of different genes. Both bind to F-actin cooperatively and induce a twist in the actin filament that results in the loss of the phalloidin-binding site. This conformational change may be responsible for the enhancement of the off rate of subunits at the minus end of ADF/cofilin-decorated filaments and for the weak filament-severing activity. Binding of ADF/cofilin is competitive with tropomyosin. Other regulatory mechanisms in animal cells include binding of phosphoinositides, phosphorylation by LIM kinases on a single serine, and changes in pH. Although vertebrate ADF/cofilins contain a nuclear localization sequence, they are usually concentrated in regions containing dynamic actin pools, such as the leading edge of migrating cells and neuronal growth cones. ADF/cofilins are essential for cytokinesis, phagocytosis, fluid phase endocytosis, and other cellular processes dependent upon actin dynamics.

The Translocon: A Dynamic Gateway at the ER Membrane

Abstract: ▪ Abstract Cotranslational protein translocation across and integration into the membrane of the endoplasmic reticulum (ER) occur at sites termed translocons. Translocons are composed of several ER membrane proteins that associate to form an aqueous pore through which secretory proteins and lumenal domains of membrane proteins pass from the cytoplasm to the ER lumen. These sites are not passive holes in the bilayer, but instead are quite dynamic both structurally and functionally. Translocons cycle between ribosome-bound and ribosome-free states, and convert between translocation and integration modes of operation. These changes in functional state are accompanied by structural rearrangements that alter translocon conformation, composition, and interactions with ligands such as the ribosome and BiP. Recent studies have revealed that the translocon is a complex and sophisticated molecular machine that regulates the movement of polypeptides through the bilayer, apparently in both directions as well as later...

Vertebrate endoderm development

Abstract: ▪ Abstract Endoderm, one of the three principal germ layers, contributes to all organs of the alimentary tract. For simplicity, this review divides formation of endodermal organs into four fundamental steps: (a) formation of endoderm during gastrulation, (b) morphogenesis of a gut tube from a sheet of cells, (c) budding of organ domains from the tube, and (d) differentiation of organ-specific cell types within the growing buds. We discuss possible mechanisms that regulate how undifferentiated endoderm becomes specified into a myriad of cell types that populate the respiratory and gastrointestinal tracts.

Adaptors for Clathrin-Mediated Traffic

Abstract: Clathrin-based systems are responsible for a large portion of vesicular traffic originating from the plasma membrane and the trans-Golgi network that reaches the endosomal compartment. The assembly of cytosolic clathrin forms the scaffold required for the local deformation of the membrane and for the formation of coated pits and vesicles. In this process, clathrin interacts in a coordinated fashion with a large number of protein partners. A subset designated clathrin adaptors links integral membrane proteins to the clathrin coat, a process that results in the recruitment of specific cargo proteins to the budding vesicle. This review focuses on the most recent advances dealing with the molecular basis for sorting by clathrin adaptors.

Vacuolar import of proteins and organelles from the cytoplasm

Abstract: ▪ Abstract Many cellular processes require a balance between protein synthesis and protein degradation. The vacuole/lysosome is the main site of protein and organellar turnover within the cell due ...

Blue-light photoreceptors in higher plants.

Abstract: ■ Abstract 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 simi- lar 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 tran- scription. 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.

Regulation of Nuclear Localization: A Key to a Door

Abstract: ▪ Abstract Information can be transferred between the nucleus and the cytoplasm by translocating macromolecules across the nuclear envelope. Communication of extracellular or intracellular changes to the nucleus frequently leads to a transcriptional response that allows cells to survive in a continuously changing environment. Eukaryotic cells have evolved ways to regulate this movement of macromolecules between the cytoplasm and the nucleus such that the transfer of information occurs only under conditions in which a transcriptional response is required. This review focuses on the ways in which cells regulate movement of proteins across the nuclear envelope and the significance of this regulation for controlling diverse biological processes.

When to Switch to Flowering

Abstract: At a certain stage in their life cycle, plants switch from vegetative to reproductive development. This transition is regulated by multiple developmental and environmental cues. These ensure that the plant switches to flowering at a time when sufficient internal resources have been accumulated and the environmental conditions are favorable. The use of a molecular genetic approach in Arabidopsis has resulted in the identification and cloning of many of the genes involved in regulating floral transition. The current view on the molecular function of these genes, their division into different genetic pathways, and how the pathways interact in a complex regulatory network are summarized.

Visual Transduction in Drosophila

Abstract: ▪ Abstract The Drosophila phototransduction cascade has emerged as an attractive paradigm for understanding the molecular mechanisms underlying visual transduction, as well as other G protein–coupled signaling cascades that are activated and terminated with great rapidity. A large collection of mutants affecting the fly visual cascade have been isolated, and the nature and function of many of the affected gene products have been identified. Virtually all of the proteins, including those that were initially classified as novel, are highly related to vertebrate homologs. Recently, it has become apparent that most of the proteins central to Drosophila phototransduction are coupled into a supramolecular signaling complex, signalplex, through association with a PDZ-containing scaffold protein. The characterization of this complex has led to a re-evaluation of the mechanisms underlying the activation and deactivation of the phototransduction cascade.

The road less traveled: emerging principles of kinesin motor utilization.

Abstract: ▪ Abstract Proteins of the kinesin superfamily utilize a conserved catalytic motor domain to generate movements in a wide variety of cellular processes. In this review, we discuss the rapid expansi...

Cell polarity in yeast.

Abstract: Subcellular asymmetry, cell polarity, is fundamental to the diverse specialized functions of eukaryotic cells. In yeast, cell polarization is essential to division and mating. As a result, this highly accessible experimental system serves as a paradigm for deciphering the molecular mechanisms underlying the generation of polarity. Beyond yeast, cell polarity is essential to the partitioning of cell fate in embryonic development, the generation of axons and their guidance during neuronal development, and the intimate communication between lymphocytes within the immune system. The polarization of yeast cells shares many features with that of these more complex examples, including regulation by both intrinsic and extrinsic cues, conserved regulatory molecules such as Cdc42 GTPase, and asymmetry of the cytoskeleton as its centerpiece. This review summarizes the molecular pathways governing the generation of cell polarity in yeast.

Molecular Mechanisms of Neural Crest Formation

Abstract: The neural crest is a transient population of multipotent precursor cells named for its site of origin at the crest of the closing neural folds in vertebrate embryos. Following neural tube closure, these cells become migratory and populate diverse regions throughout the embryo where they give rise to most of the neurons and support cells of the peripheral nervous system (PNS), pigment cells, smooth muscle, craniofacial cartilage, and bone. Because of its remarkable ability to generate such diverse derivatives, the neural crest has fascinated developmental biologists for over one hundred years. A great deal has been learned about the migratory pathways neural crest cells follow and the signals that may trigger their differentiation, but until recently comparatively little was known about earlier steps in neural crest development. In the past few years progress has been made in understanding these earlier events, including how the precursors of these multipotent cells are specified in the early embryo and the mechanisms by which they become migratory. In this review, we first examine the mechanisms underlying neural crest induction, paying particular attention to a number of growth factor and transcription factor families that have been implicated in this process. We also discuss when and how the fate of neural crest precursors may diverge from those of nearby neural and epidermal populations. Finally, we review recent advances in our understanding of how neural crest cells become migratory and address the process of neural crest diversification.

Synaptic vesicle biogenesis.

Abstract: ▪ Abstract Synaptic vesicles, which have been a paradigm for the fusion of a vesicle with its target membrane, also serve as a model for understanding the formation of a vesicle from its donor membrane. Synaptic vesicles, which are formed and recycled at the periphery of the neuron, contain a highly restricted set of neuronal proteins. Insight into the trafficking of synaptic vesicle proteins has come from studying not only neurons but also neuroendocrine cells, which form synaptic-like microvesicles (SLMVs). Formation and recycling of synaptic vesicles/SLMVs takes place from the early endosome and the plasma membrane. The cytoplasmic machinery of synaptic vesicle/SLMV formation and recycling has been studied by a variety of experimental approaches, in particular using cell-free systems. This has revealed distinct machineries for membrane budding and fission. Budding is mediated by clathrin and clathrin adaptors, whereas fission is mediated by dynamin and its interacting protein SH3p4, a lysophosphatidic ...

Integration of signaling networks that regulate Dictyostelium differentiation.

Abstract: ▪ Abstract In Dictyostelium amoebae, cell-type differentiation, spatial patterning, and morphogenesis are controlled by a combination of cell-autonomous mechanisms and intercellular signaling. A chemotactic aggregation of ∼105 cells leads to the formation of a multicellular organism. Cell-type differentiation and cell sorting result in a small number of defined cell types organized along an anteroposterior axis. Finally, a mature fruiting body is created by the terminal differentiation of stalk and spore cells. Analysis of the regulatory program demonstrates a role for several molecules, including GSK-3, signal transducers and activators of transcription (STAT) factors, and cAMP-dependent protein kinase (PKA), that control spatial patterning in metazoans. Unexpectedly, two component systems containing histidine kinases and response regulators also play essential roles in controlling Dictyostelium development. This review focuses on the role of cAMP, which functions intracellularly to mediate the activity ...

Cooperation between microtubule- and actin-based motor proteins.

Abstract: ▪ Abstract Organelle transport has been proposed to proceed in two steps: long-range transport along microtubules and local delivery via actin filaments. This model is supported by recent studies o...

Actin-related proteins

Abstract: ▪ Abstract Actin-related proteins (Arps) participate in a diverse array of cellular processes. They modulate assembly of conventional actin, contribute to microtubule-based motility catalyzed by dy...

[PSI+]: An Epigenetic Modulator of Translation Termination Efficiency

Abstract: ▪ Abstract The [PSI+] factor of the yeast Saccharomyces cerevisiae is an epigenetic regulator of translation termination. More than three decades ago, genetic analysis of the transmission of [PSI+] revealed a complex and often contradictory series of observations. However, many of these discrepancies may now be reconciled by a revolutionary hypothesis: protein conformation-based inheritance (the prion hypothesis). This model predicts that a single protein can stably exist in at least two distinct physical states, each associated with a different phenotype. Propagation of one of these traits is achieved by a self-perpetuating change in the protein from one form to the other. Mounting genetic and biochemical evidence suggests that the determinant of [PSI+] is the nuclear encoded Sup35p, a component of the translation termination complex. Here we review the series of experiments supporting the yeast prion hypothesis and provide another look at the 30 years of work preceding this theory in light of our curren...

Mechanisms of Viral Interference with MHC Class I Antigen Processing and Presentation

Abstract: Viruses are ubiquitous and dangerous obligate intracellular parasites. To facilitate recognition of virus-infected cells by the immune system, vertebrates evolved a system that displays oligopeptides derived from viral proteins on the surface of cells in association with class I molecules of the major histocompatibility complex. Here we review the mechanisms counter-evolved by viruses to interfere with the generation of viral peptides, their intracellular trafficking, or the cell surface expression of class I molecules bearing viral peptides. This topic is important in its own right because the viruses that encode these proteins represent medically important pathogens, are potential vectors for vaccines or gene therapy, and provide strategies and tools for blocking immune recognition in transplantation, autoimmunity, and gene therapy. In addition, studies on viral interference provide unique insights into unfettered antigen processing and normal cellular functions that are exploited and exaggerated by viruses.

Lymphocyte Survival—The Struggle Against Death

Abstract: ▪ Abstract Cell proliferation and cell death must be closely regulated to maintain the integrity of the immune system during the lifetime of multicellular organisms. Proliferative expansion of lymphoid cells is required for effective immune responses against invading microorganisms. However, following infection eradication, expanded effector cells must be eliminated to prevent non-adaptive accumulation of cells. Therefore, higher vertebrates have developed an extensive network of signal transduction pathways that allow integration of cell survival and cell death stimuli. This network functions to ensure the controlled activation and expansion of cells during an immune response and the deletion of lymphoid cells that are no longer needed at the end of an immune response. Extracellular signals appear to control both mechanisms. Ultimate responses are integrated through cell surface receptors that are linked to intracellular signaling cascades. These signal transduction pathways converge to regulate cell fat...