Commentary
Abstract
Mitral valve prolapse (MVP), an abnormal displacement into the left atrium of a thickened and redundant mitral valve during systole, is a relatively frequent abnormality in humans and may be associated with serious complications. A recent study implicates fibrillin-1, a component of extracellular matrix microfibrils, in the pathogenesis of a murine model of MVP. This investigation represents an initial step toward understanding the mechanisms involved in human MVP disease and the development of potential treatments.
Authors
Arthur E. Weyman, Marielle Scherrer-Crosbie
Abstract
Studies in genetically engineered mice have shown the importance of cross-talk between organs in the regulation of energy metabolism. In this issue, a careful metabolic characterization of mice with genetic deficiency of the GLUT4 glucose transporter in adipocytes and muscle is reported. These mice compensate for decreased peripheral glucose disposal by increasing hepatic glucose uptake and lipid synthesis as well as by increasing lipid utilization in peripheral tissues. These findings are relevant to humans with type 2 diabetes, in whom a key feature is diminished peripheral glucose disposal.
Authors
Perry E. Bickel
Abstract
Polycystin-1, the protein encoded by the principal gene involved in autosomal dominant polycystic kidney disease, has been implicated in extracellular sensing as well as in cell-cell and cell-matrix interactions. However, the precise mechanisms involved in polycystin-1 signaling are not well defined. A report in this issue of the JCI demonstrates that the C-terminal tail of polycystin-1 is cleaved from the membrane through regulated intramembrane proteolysis (RIP) and that this domain translocates to the nucleus, where it activates the AP-1 transcription pathway. This translocation appears to be modulated by polycystin-2, with which polycystin-1 is thought to interact. These findings provide what we believe to be the first evidence that polycystin-1 can signal directly to the nucleus and that polycystin-1–polycystin-2 interactions do not require colocalization of these proteins in the same membrane compartment.
Authors
Lisa M. Guay-Woodford
Abstract
Autosomal dominant disorders of the skin may present in a pattern following the lines of embryologic development of the ectoderm. In these cases, the surrounding skin is normal, and molecular studies have shown that the causative mutation is confined to the affected ectodermal tissue (type 1 mosaicism). Rarely, an individual shows skin lesions that follow the pattern of type 1 mosaicism, but the rest of the skin shows a milder form of the disorder (type 2 mosaicism). A new study provides the molecular basis for type 2 mosaicism .
Authors
Amy S. Paller
Abstract
SCID, a syndrome characterized by the absence of T cells and adaptive immunity, can result from mutations in multiple genes that encode components of the immune system. Three such components are cytokine receptor chains or signaling molecules, five are needed for antigen receptor development, one is adenosine deaminase — a purine salvage pathway enzyme, and the last is a phosphatase, CD45. In this issue of the JCI, a report describes how complete deficiency of the CD3ε chain of the T cell antigen receptor/CD3 complex causes human SCID.
Authors
Rebecca H. Buckley
Abstract
There have been exciting recent advances in our understanding of the structural and molecular biology of the glomerular slit diaphragm, as described in a report in this issue of the JCI. These findings, combined with data on the permeability of the basement membrane and evidence that the endothelium may be a more important barrier than often supposed, are allowing a clearer understanding to emerge of how the 3 parts of the glomerular capillary wall jointly determine its functional properties.
Authors
William M. Deen
Abstract
The Randle cycle, which has been invoked to explain the reciprocal relationship between fatty acid oxidation and glucose oxidation, has long been implicated as a potential mechanism for hyperglycemia and type 2 diabetes mellitus (T2DM). Now genetic, functional genomic, and transgenic approaches have identified PPARγ coactivators (PGC-1α and PGC-1β) as key regulators of mitochondrial number and function. They regulate adaptive thermogenesis as well as glucose and fat oxidation in muscle and fat tissue, gluconeogenesis in liver, and even glucose-regulated insulin secretion in β cells. PGC-1α and PGC-1β mRNA levels and the mitochondrial genes they regulate are decreased in muscle of people with prediabetes and T2DM. A new report indicates that PGC-1α and PGC-1β mRNA levels decrease with age in individuals with a genetic variant in PGC-1α, and these decreases correlate with alterations in whole-body glucose and fatty acid oxidation. These findings provide insights into how aging modifies genetic susceptibility to alterations in oxidative phosphorylation and T2DM.
Authors
Alan R. Shuldiner, John C. McLenithan
Abstract
Kinase suppressor of Ras-1 (KSR1) is a recently identified member of the EGFR–Ras–Raf-1–MAPK signaling pathway. A new study demonstrates that KSR1 protects intestinal epithelium from TNF-α–induced apoptosis, abrogating inflammatory bowel disease (IBD). Since its discovery, there has been disagreement as to whether KSR1 possesses intrinsic kinase activity. Using transgenic mouse models and genetically modified mouse colon epithelial cells, Polk and coworkers show that the kinase activity of KSR1 is off in normal colon epithelial cells, becoming activated only at the onset of IBD. They also provide strong evidence that KSR1 kinase activity is essential for anti-apoptotic protection of the intestinal epithelium. These new data in support of KSR1 as a kinase highlight an ongoing debate as to whether KSR1 does indeed serve as a specific kinase in transphosphorylating and transactivating c-Raf–1 toward MEK1.
Authors
Richard Kolesnick, H. Rosie Xing
Abstract
Cellular senescence induced by different stresses and telomere shortening appears to play an important role in the aging process. The products of the INK4a/ARF locus — p16INK4a and ARF — arrest cell proliferation at the senescence stage by exerting their effects on retinoblastoma protein– and p53-mediated responsive pathways. A study in this issue of the JCI provides experimental evidence of a specific upregulation of these cell cycle inhibitors in a variety of organs during mammalian aging.
Authors
Ande Satyanarayana, K. Lenhard Rudolph
Abstract
DNA vaccination is a novel immunization strategy that has great potential for the development of vaccines and immune therapeutics. This strategy has been highly effective in mice, while less immunogenic in nonhuman primates and humans. Enhancing DNA vaccine potency remains a challenge. It is likely that APCs, and especially DCs, play a paramount role in the presentation of vaccine antigen to the immune system. A new study reports the synergistic recruitment, expansion, and activation of DCs in vivo in a mouse model through covaccination with plasmids encoding macrophage inflammatory protein-1α (MIP-1α), fms-like tyrosine kinase 3 ligand (Flt3L), and the DNA vaccine. Such cooperative strategies delivering vaccine in a single, simple platform result in improved cellular immunity in vivo, including enhanced tetramer responses and IFN-γ secretion by antigen-specific cells.
Authors
Michele A. Kutzler, David B. Weiner
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