Medicine and Health Sciences Commons^™

Alzheimer's Therapeutics Targeting Amyloid Beta 1–42 Oligomers Ii: Sigma-2/Pgrmc1 Receptors Mediate Abeta 42 Oligomer Binding And Synaptotoxicity, Nicholas J. Izzo, Jinbin Xu, Chenbo Zeng, Molly J. Kirk, Kelsie Mozzoni, Colleen Silky, Courtney Rehak, Raymond Yurko, Gary Look, Gilbert Rishton, Hank Safferstein, Carlos Cruchaga, Alison Goate, Michael A. Cahill, Ottavio Arancio, Robert H. Mach, Rolf Craven, Elizabeth Head, Harry Levine Iii, Tara L. Spires-Jones, Susan M. Catalano

Sanders-Brown Center on Aging Faculty Publications

Amyloid beta (Abeta) 1-42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic …

Alzheimer's Therapeutics Targeting Amyloid Beta 1-42 Oligomers I: Abeta 42 Oligomer Binding To Specific Neuronal Receptors Is Displaced By Drug Candidates That Improve Cognitive Deficits, Nicholas J. Izzo, Agnes Staniszewski, Lillian To, Mauro Fa, Andrew F. Teich, Faisal Saeed, Harrison Wostein, Thomas Walko Iii, Anisha Vaswani, Meghan Wardius, Zanobia Syed, Jessica Ravenscroft, Kelsie Mozzoni, Colleen Silky, Courtney Rehak, Raymond Yurko, Patricia Finn, Gary Look, Gilbert Rishton, Hank Safferstein, Miles Miller, Conrad Johanson, Edward Stopa, Manfred Windisch, Birgit Hutter-Paier, Mehrdad Shamloo, Ottavio Arancio, Harry Levine Iii, Susan M. Catalano

Sanders-Brown Center on Aging Faculty Publications

Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1-42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce …

Latexin Sensitizes Leukemogenic Cells To Gamma-Irradiation-Induced Cell-Cycle Arrest And Cell Death Through Rps3 Pathway, Y. You, R. Wen, R. Pathak, A. Li, W. Li, D. St. Clair, M. Hauer-Jensen, D. Zhou, Ying Liang

Toxicology and Cancer Biology Faculty Publications

Leukemia is a leading cause of cancer death. Recently, the latexin (Lxn) gene was identified as a potential tumor suppressor in several types of solid tumors and lymphoma, and Lxn expression was found to be absent or downregulated in leukemic cells. Whether Lxn functions as a tumor suppressor in leukemia and what molecular and cellular mechanisms are involved are unknown. In this study, the myeloid leukemogenic FDC-P1 cell line was used as a model system and Lxn was ectopically expressed in these cells. Using the protein pull-down assay and mass spectrometry, ribosomal protein subunit 3 (Rps3) was identified as a …

Adrenergic Signaling Regulates Mitochondrial Ca2+ Uptake Through Pyk2-Dependent Tyrosine Phosphorylation Of The Mitochondrial Ca2+ Uniporter., Jin O-Uchi, Bong Sook Jhun, Shangcheng Xu, Stephen Hurst, Anna Raffaello, Xiaoyun Liu, Bing Yi, Huiliang Zhang, Polina Gross, Jyotsna Mishra, Alina Ainbinder, Sarah Kettlewell, Godfrey L Smith, Robert T Dirksen, Wang Wang, Rosario Rizzuto, Shey-Shing Sheu

Department of Medicine Faculty Papers

AIMS: Mitochondrial Ca2+ homeostasis is crucial for balancing cell survival and death. The recent discovery of the molecular identity of the mitochondrial Ca2+ uniporter pore (MCU) opens new possibilities for applying genetic approaches to study mitochondrial Ca2+ regulation in various cell types, including cardiac myocytes. Basal tyrosine phosphorylation of MCU was reported from mass spectroscopy of human and mouse tissues, but the signaling pathways that regulate mitochondrial Ca2+ entry through posttranslational modifications of MCU are completely unknown. Therefore, we investigated α1-adrenergic-mediated signal transduction of MCU posttranslational modification and function in cardiac cells.

RESULTS: α1-adrenoceptor (α1-AR) signaling translocated activated proline-rich tyrosine …

Rorα Binds To E2f1 To Inhibit Cell Proliferation And Regulate Mammary Gland Branching Morphogenesis, Gaofeng Xiong, Ren Xu

Markey Cancer Center Faculty Publications

Retinoic acid receptor-related orphan nuclear receptor alpha (RORα) is a potent tumor suppressor that reduces cell proliferation and inhibits tumor growth. However, the molecular mechanism by which it inhibits cell proliferation remains unknown. We demonstrate a noncanonical nuclear receptor pathway in which RORα binds to E2F1 to inhibit cell cycle progression. We showed that RORα bound to the heptad repeat and marked box region of E2F1 and suppressed E2F1-regulated transcription in epithelial cells. Binding of RORα inhibited E2F1 acetylation and its DNA-binding activity by recruiting histone deacetylase 1 (HDAC1) to the protein complexes. Knockdown of HDAC1 or inhibition of HDAC …

The Rak/Frk Tyrosine Kinase Associates With And Internalizes The Epidermal Growth Factor Receptor, Ling Jin, Rolf J. Craven

Pharmacology and Nutritional Sciences Faculty Publications

Src is the founding member of a diverse family of intracellular tyrosine kinases, and Src has a key role in promoting cancer growth, in part, through its association with receptor tyrosine kinases. However, some Src-related proteins have widely divergent physiological roles, and these proteins include the Rak/Frk tyrosine kinase (Frk stands for Fyn-related kinase), which inhibits cancer cell growth and suppresses tumorigenesis. Rak/Frk phosphorylates and stabilizes the Pten tumor suppressor, protecting it from degradation, and Rak/Frk associates with the retinoblastoma (Rb) tumor suppressor. However, the role of Rak/Frk in receptor-mediated signaling is largely unknown. Here, we demonstrate that Rak/Frk associates …

Broad And Direct Interaction Between Tlr And Siglec Families Of Pattern Recognition Receptors And Its Regulation By Neu1., Guo-Yun Chen, Nicholas K. Brown, Wei Wu, Zahra Khedri, Hai Yu, Xi Chen, Diantha Van De Vlekkert, Alessandra D'Azzo, Pan Zheng, Yang Liu

Pediatrics Faculty Publications

Both pathogen- and tissue damage-associated molecular patterns induce inflammation through toll-like receptors (TLRs), while sialic acid-binding immunoglobulin superfamily lectin receptors (Siglecs) provide negative regulation. Here we report extensive and direct interactions between these pattern recognition receptors. The promiscuous TLR binders were human SIGLEC-5/9 and mouse Siglec-3/E/F. Mouse Siglec-G did not show appreciable binding to any TLRs tested. Correspondingly, Siglece deletion enhanced dendritic cell responses to all microbial TLR ligands tested, while Siglecg deletion did not affect the responses to these ligands. TLR4 activation triggers Neu1 translocation to cell surface to disrupt TLR4:Siglec-E interaction. Conversely, sialidase inhibitor Neu5Gc2en prevented TLR4 ligand-induced …