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Newly synthesized proteins en route to the Golgi apparatus are exported from the endoplasmic reticulum by COPII coated vesicles. Fath et al. (2007) now reveal the structure of a large portion of the yeast Sec13/31 complex, which comprises the coat framework of COPII-coated vesicles. Their findings suggest a mechanism by which the COPII cage assembles and accommodates cargo of different sizes.
COPII-coated vesicles export newly synthesized proteins from the endoplasmic reticulum. The COPII coat consists of the Sec23/24-Sar1 complex that selects cargo and the Sec13/31 assembly unit that can polymerize into an octahedral cage and deform the membrane into a bud. Crystallographic analysis of the assembly unit reveals a 28 nm long rod comprising a central α-solenoid dimer capped by two β-propeller...
The mammalian cilium protrudes from the apical/lumenal surface of polarized cells and acts as a sensor of environmental cues. Numerous developmental disorders and pathological conditions have been shown to arise from defects in cilia-associated signaling proteins. Despite mounting evidence that cilia are essential sites for coordination of cell signaling, little is known about the cellular mechanisms...
Protein kinases control cellular decision processes by phosphorylating specific substrates. Thousands of in vivo phosphorylation sites have been identified, mostly by proteome-wide mapping. However, systematically matching these sites to specific kinases is presently infeasible, due to limited specificity of consensus motifs, and the influence of contextual factors, such as protein scaffolds, localization,...
Neurosecretory control centers form part of the forebrain in many animal phyla, including vertebrates, insects, and annelids. The evolutionary origin of these centers is largely unknown. To identify conserved, and thus phylogenetically ancient, components of neurosecretory brain centers, we characterize and compare neurons that express the prohormone vasotocin (vasopressin/oxytocin)-neurophysin in...
The immortal strand hypothesis posits that the propensity of stem cell compartments to give rise to cancer in later life can be minimized if stem cells, during the process of self-renewal, retain those DNA strands with the fewest mutations acquired during DNA replication. In this Essay, I explore evidence in support of the hypothesis, the biological implications, and the key questions that remain...
Endoplasmic reticulum (ER) stress caused by misfolded proteins or cytotoxic drugs can kill cells and although activation of this pathway has been implicated in the etiology of certain degenerative disorders its mechanism remains unresolved. Bim, a proapoptotic BH3-only member of the Bcl-2 family is required for initiation of apoptosis induced by cytokine deprivation or certain stress stimuli. Its...
Helicases are molecular motors that separate DNA strands for efficient replication of genomes. We probed the kinetics of individual ring-shaped T7 helicase molecules as they unwound double-stranded DNA (dsDNA) or translocated on single-stranded DNA (ssDNA). A distinctive DNA sequence dependence was observed in the unwinding rate that correlated with the local DNA unzipping energy landscape. The unwinding...
Mesenchymal stem cells (MSCs) are defined as cells that undergo sustained in vitro growth and are able to give rise to multiple mesenchymal lineages. Although MSCs are already used in regenerative medicine little is known about their in vivo behavior and developmental derivation. Here, we show that the earliest wave of MSC in the embryonic trunk is generated from Sox1 + neuroepithelium but...
It is not clear to what extent noncoding RNAs regulate the homeobox (HOX) genes that encode key regulators of development in the embryo. In this issue, Rinn et al. (2007) characterize noncoding RNAs that regulate HOX genes and discover one, HOTAIR, that unexpectedly regulates a HOX gene cluster on a different chromosome than the HOX cluster that encodes it.
The X-linked Foxp3 is a member of the forkhead/winged helix transcription factor family. Germline mutations cause lethal autoimmune diseases in males. Serendipitously, we observed that female mice heterozygous for the “scurfin” mutation of the Foxp3 gene (Foxp3 sf/+ ) developed cancer at a high rate. The majority of the cancers were mammary carcinomas in which the wild-type Foxp3 allele was...
The serine/threonine kinase Akt, also known as protein kinase B (PKB), is a central node in cell signaling downstream of growth factors, cytokines, and other cellular stimuli. Aberrant loss or gain of Akt activation underlies the pathophysiological properties of a variety of complex diseases, including type-2 diabetes and cancer. Here, we review the molecular properties of Akt and the approaches used...
Increased expression of the epidermal growth factor receptor HER-2/ErbB2 is frequently observed in breast cancer and is targeted by the anticancer drug Herceptin. Now, Zuo et al. (2007) reveal that an X-linked gene encoding the transcription factor FOXP3 is a breast cancer tumor suppressor that represses expression of HER2/ErbB2.
Assembly of the nonmotile primary cilium of vertebrate cells requires one of the centrioles of the centrosome. A cluster of new studies, including one in this issue of Cell by Pugacheva et al. (2007), reveal that ciliary assembly proteins influence cell-cycle progression and that a centrosomal “mitotic kinase” promotes ciliary disassembly. The link between the cell cycle and the primary cilium may...
The cardiac conduction system is an anatomically discrete segment of specialized myocardium that initiates and propagates electrical impulses to coordinate myocardial contraction. To define the molecular composition of the mouse ventricular conduction system we used microdissection and transcriptional profiling by serial analysis of gene expression (SAGE). Conduction-system-specific expression for...
M. tuberculosis and M. leprae are considered to be prototypical intracellular pathogens that have evolved strategies to enable growth in the intracellular phagosomes. In contrast, we show that lysosomes rapidly fuse with the virulent M. tuberculosis- and M. leprae-containing phagosomes of human monocyte-derived dendritic cells and macrophages. After 2 days, M. tuberculosis progressively translocates...
This issue's Molecular Medicine Select describes recent progress in identifying pathways that dampen inflammation in multiple disease contexts including allergic skin reactions, demyelinating diseases, and neurodegeneration. In addition to revealing new potential therapeutic targets, these efforts also put a spotlight on small molecules, including cannabinoids and compounds derived from omega-3 fatty...
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