Commentary
Abstract
Inositol-requiring enzyme 1 (IRE1) is a transmembrane protein that signals from the ER and contributes to the generation of an active spliced form of the transcriptional regulator X-box–binding protein 1 (XBP1). XBP1 is required for the terminal differentiation of B lymphocytes into plasma cells, and IRE1 also participates in this differentiation event. A study in this issue of the JCI reveals, quite unexpectedly, that IRE1 is also required early in B lymphocyte development for the induction of the machinery that mediates Ig gene rearrangement.
Authors
Shiv Pillai
Abstract
In pancreatic β cells, not only insulin exocytosis per se, but translocation of β granules toward the plasma membrane — an event upstream of exocytosis — are under the control of glucose. However, the molecular basis of this translocation has been poorly understood. Rab27a-mediated translocation of glucose-induced β granules is reported in this issue of the JCI. Rab27a or its effector molecule may constitute a novel pharmacological target because potentiation of the Rab27a pathway is expected to restore β cell glucose competency in patients with diabetes mellitus.
Authors
Toru Aizawa, Mitsuhisa Komatsu
Abstract
The potential threat of the smallpox virus as a bioterror weapon has long been recognized, and the need for developing suitable countermeasures has become especially acute following the events of September 2001. Traditional antiviral agents interfere with viral proteins or functions. In a new study, Yang et al. focus instead on host cellular pathways used by the virus. A drug that interferes with the cellular ErbB-1 signal transduction pathway, activated by smallpox growth factor, sheds new light on how the virus replicates in the cell. Drugs that target the ErbB-signaling pathways represent a promising new class of antiviral agents.
Authors
Anthony S. Fauci, Mark D. Challberg
Abstract
The growth hormone/IGF-1–signaling (GH/IGF-1–signaling) system is involved in numerous physiological processes during normal growth and development and also in the aging process. Understanding the regulation of this system is therefore of importance to the biologist. Studies conducted over the past decade have shown that the JAK/STAT pathways are involved in GH signaling to the nucleus. More recently, evidence has been presented that a member of the SOCS family, SOCS2, is a negative regulator of GH signaling. This story began several years ago with the dramatic demonstration of gigantism in the SOCS2-knockout mouse. A more specific definition of the role of SOCS2 in GH signaling is provided in this issue of the JCI by the demonstration that the overgrowth phenotype of the SOCS2–/– mouse is dependent upon the presence of endogenous GH and that administration of GH to mice lacking both endogenous GH and SOCS2 produced excessive growth.
Authors
Derek LeRoith, Peter Nissley
Abstract
Adenosine is a ubiquitous biological mediator with the capacity to produce both pro- and anti-inflammatory effects in tissues. Proinflammatory and bronchoconstrictive actions of adenosine in the asthmatic lung are well recognized, with the latter being mediated, in part, through A1 receptor activation on airway smooth muscle. In this issue of the JCI, Sun et al. report findings in adenosine deaminase–deficient mice that suggest the occurrence of anti-inflammatory actions of adenosine in the lung, mediated through A1 adenosine receptors on macrophages. Here we discuss the history of the study of adenosine receptor ligands for asthma and how enhanced understanding of adenosine receptor biology may aid in the rational exploitation of these receptors as therapeutic targets.
Authors
Stephen L. Tilley, Richard C. Boucher
Abstract
Insulin secretion is critically dependent on the proper function of a complex molecular network. CaV2.3-knockout (CaV2.3–/–) and PKCλ-knockout (PKCλ–/–) mouse models now suggest that these 2 players, the Cav2.3 channel and PKCλ, are important constituents of this molecular network. Subsequent to glucose stimulation, insulin is released from the pancreatic β cell in a biphasic pattern, i.e., a rapid initial phase followed by a slower, more sustained phase. Interestingly, Ca2+ influx through the CaV2.3 channel regulates only the second phase of insulin secretion. PKCλ seems to enter the β cell nucleus and in turn modulates the expression of several genes critical for β cell secretory function. Studies by Hashimoto et al. and Jing et al. in this issue of the JCI set out to answer the question of why numerous isoforms of proteins with similar functions are present in the β cell. This is important, since it has been difficult to understand the modulatory and/or regulatory roles of different isoforms of proteins in defined subcellular compartments and at various times during the secretory process in both β cell physiology and pathophysiology.
Authors
Shao-Nian Yang, Per-Olof Berggren
Abstract
In this issue of the JCI, Ciampi et al. report the identification of a novel oncogene in patients affected by radiation-associated thyroid papillary carcinomas. This oncogene derives from a paracentric inversion of the long arm of chromosome 7, which results in an in-frame fusion of the N-terminus of the A-kinase anchor protein 9 (AKAP9) gene with the C-terminal catalytic domain (exons 9–18) of the serine-threonine kinase BRAF. The resulting AKAP9-BRAF fusion protein shows constitutive kinase activity, and it is able to transmit mitogenic signals to the MAPK pathways and to promote malignant transformation of NIH3T3 cells.
Authors
Alfredo Fusco, Giuseppe Viglietto, Massimo Santoro
Abstract
Neurotransplantation as a treatment for Parkinson disease reached the stage of human trials over 15 years ago, but the field, which is still in its infancy, has encountered a number of roadblocks since then, both political and scientific. With hope that stem cells may be used as a new source of dopaminergic neurons to replace the degenerating nerve cells in Parkinson disease looming, it is critical that we learn from the past as we work toward achieving new milestones aimed at making this new therapeutic strategy a reality. One of those milestones, which is an important translational step in the development of stem cell technology and the subject of a report in this issue of the JCI, involves transplanting new dopaminergic cell lines to a primate model of Parkinson disease.
Authors
J. William Langston
Abstract
For several decades, intravenous Ig has been used as treatment for a variety of immune-related diseases, including immune thrombocytopenic purpura (ITP), autoimmune neuropathies, systemic lupus erythematosus, myasthenia gravis, Guillain-Barré syndrome, skin blistering syndromes, and Kawasaki disease. Despite years of use, its mechanism of immunomodulation is still unclear. Recent studies using mouse models of ITP and arthritis, including one reported in this issue of the JCI, now provide some insights into this mechanism and the rationale for the development of Fcγ receptor–targeted therapeutics.
Authors
Raphael Clynes
Abstract
Stromal cell–derived factor–1 (SDF-1) is a chemokine with unique functions, including a role in the trafficking of primitive blood precursor cells. A better understanding at a molecular level of how the binding of SDF-1 to its cell surface receptor, CXCR4, elicits specific biological responses in these cells has now been achieved through the identification of PKC-ζ activation as a common downstream signal. This finding suggests that treatment of a variety of clinical conditions might benefit from the targeting of PKC-ζ.
Authors
Connie J. Eaves
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