Wayne State University

About: Wayne State University is a education organization based out in Detroit, Michigan, United States. It is known for research contribution in the topics: Population & Cancer. The organization has 42801 authors who have published 82738 publications receiving 3083713 citations. The organization is also known as: WSU & Wayne University.

Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle.

Abstract: Studies of yeast have shown that the SIR2 gene family is involved in chromatin structure, transcriptional silencing, DNA repair, and control of cellular life span. Our functional studies of human SIRT2, a homolog of the product of the yeast SIR2 gene, indicate that it plays a role in mitosis. The SIRT2 protein is a NADdependent deacetylase (NDAC), the abundance of which increases dramatically during mitosis and is multiply phosphorylated at the G2/M transition of the cell cycle. Cells stably overexpressing the wild-type SIRT2 but not missense mutants lacking NDAC activity show a marked prolongation of the mitotic phase of the cell cycle. Overexpression of the protein phosphatase CDC14B, but not its close homolog CDC14A, results in dephosphorylation of SIRT2 with a subsequent decrease in the abundance of SIRT2 protein. A CDC14B mutant defective in catalyzing dephosphorylation fails to change the phosphorylation status or abundance of SIRT2 protein. Addition of 26S proteasome inhibitors to human cells increases the abundance of SIRT2 protein, indicating that SIRT2 is targeted for degradation by the 26S proteasome. Our data suggest that human SIRT2 is part of a phosphorylation cascade in which SIRT2 is phosphorylated late in G2, during M, and into the period of cytokinesis. CDC14B may provoke exit from mitosis coincident with the loss of SIRT2 via ubiquitination and subsequent degradation by the 26S proteasome. As the founding member of a vast gene family with members present in archaebacteria, eubacteria, and eukaryotes, SIR2 was first described in the budding yeast as a gene mediating the transcriptional silencing of the silent mating type (MAT) loci HML and HMR (14, 19). Additional functions for SIR2 in budding have been described, including the silencing of subtelomeric genes (telomere position effect [TPE]) and the regulation of transcription and recombination in the multiple tandem copies of ribosomal DNA (rDNA) (for a review, see reference 12). Guarente, Sinclair, and coworkers have shown that the SIR2 gene may suppress aging in budding yeast, through a mechanism involving the suppression of extrachromosomal rDNA circles (ERCs) derived from errant intralocus recombination and suggested that SIR2-related genes in other organisms may be involved in the aging process as well, even in multicellular eukaryotes (13). The mechanism by which SIRT (an acronym for SIR2 related) genes retard aging in metazoans may involve caloric restriction (CR) instead of the ERCs found in yeast (22). Support for this hypothesis has recently come from the key finding that providing the nematode Caenorhabditis elegans with two copies of one of its SIR2-related genes (the gene normally found on chromosome IV) can extend the worm’s life span by 50% (36). This extension of life span function is seen only for one of the three SIR2-related genes, Sir-2.1, encoding a large nuclear protein orthologous to that coded for by the SIR2-related gene known as SIRT1 in humans and SIR2 in mice. Neither of the other two SIRT genes in the

Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J

Abstract: The appearance of a spontaneous mutation in mice in a University of Michigan research laboratory has led to the identification of the gene responsible for a form of the inherited neurodegenerative disease called Charcot–Marie–Tooth disorder. The pale tremor mice, which develop a multi-organ neurodegeneration, are mutated in a homologue of the yeast gene Fig4, which is required to maintain normal levels of the signalling lipid PtdIns(3,5)P2. Prior to this work, there had been no indication that the low abundance signalling compound PtdIns(3,5)P2 had a specific role in neuronal maintenance. This manuscript provides A first description of a new spontaneous mouse mutant, called pale tremor, with a retrotransposon inserted into the gene encoding the phosphatidylinositol-3,5-bisphosphate 5-phosphatase (PtdIns(3,5)P2) Fig4. The phenotype includes early neurodegeneration, abnormal pigmentation, altered phosphoinositide levels, and the presence of large vacuoles in affected cells. Membrane-bound phosphoinositides are signalling molecules that have a key role in vesicle trafficking in eukaryotic cells1. Proteins that bind specific phosphoinositides mediate interactions between membrane-bounded compartments whose identity is partially encoded by cytoplasmic phospholipid tags. Little is known about the localization and regulation of mammalian phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), a phospholipid present in small quantities that regulates membrane trafficking in the endosome–lysosome axis in yeast2. Here we describe a multi-organ disorder with neuronal degeneration in the central nervous system, peripheral neuronopathy and diluted pigmentation in the ‘pale tremor’ mouse. Positional cloning identified insertion of ETn2β (early transposon 2β)3 into intron 18 of Fig4 (A530089I17Rik), the homologue of a yeast SAC (suppressor of actin) domain PtdIns(3,5)P2 5-phosphatase located in the vacuolar membrane. The abnormal concentration of PtdIns(3,5)P2 in cultured fibroblasts from pale tremor mice demonstrates the conserved biochemical function of mammalian Fig4. The cytoplasm of fibroblasts from pale tremor mice is filled with large vacuoles that are immunoreactive for LAMP-2 (lysosomal-associated membrane protein 2), consistent with dysfunction of the late endosome–lysosome axis. Neonatal neurodegeneration in sensory and autonomic ganglia is followed by loss of neurons from layers four and five of the cortex, deep cerebellar nuclei and other localized brain regions. The sciatic nerve exhibits reduced numbers of large-diameter myelinated axons, slowed nerve conduction velocity and reduced amplitude of compound muscle action potentials. We identified pathogenic mutations of human FIG4 (KIAA0274) on chromosome 6q21 in four unrelated patients with hereditary motor and sensory neuropathy. This novel form of autosomal recessive Charcot–Marie–Tooth disorder is designated CMT4J.

Observation of the rare B-s(0)->mu(+)mu(-) decay from the combined analysis of CMS and LHCb data

Abstract: The standard model of particle physics describes the fundamental particles and their interactions via the strong, electromagnetic and weak forces. It provides precise predictions for measurable quantities that can be tested experimentally. The probabilities, or branching fractions, of the strange B meson (B-s(0)) and the B-0 meson decaying into two oppositely charged muons (mu(+) and mu(-)) are especially interesting because of their sensitivity to theories that extend the standard model. The standard model predicts that the B-s(0)->mu(+)mu(-) and B-0 ->mu(+)mu(-) decays are very rare, with about four of the former occurring for every billion B-s(0) mesons produced, and one of the latter occurring for every ten billion B-0 mesons(1). A difference in the observed branching fractions with respect to the predictions of the standard model would provide a direction in which the standard model should be extended. Before the Large Hadron Collider (LHC) at CERN2 started operating, no evidence for either decay mode had been found. Upper limits on the branching fractions were an order of magnitude above the standard model predictions. The CMS (Compact Muon Solenoid) and LHCb(Large Hadron Collider beauty) collaborations have performed a joint analysis of the data from proton-proton collisions that they collected in 2011 at a centre-of-mass energy of seven teraelectronvolts and in 2012 at eight teraelectronvolts. Here we report the first observation of the B-s(0)->mu(+)mu(-) decay, with a statistical significance exceeding six standard deviations, and the best measurement so far of its branching fraction. Furthermore, we obtained evidence for the B-0 ->mu(+)mu(-) decay with a statistical significance of three standard deviations. Both measurements are statistically compatible with standard model predictions and allow stringent constraints to be placed on theories beyond the standard model. The LHC experiments will resume taking data in 2015, recording proton-proton collisions at a centre-of-mass energy of 13 teraelectronvolts, which will approximately double the production rates of B-s(0) and B-0 mesons and lead to further improvements in the precision of these crucial tests of the standard model.