Digital Commons Network^™

Protein Synthesis Required For Long-Term Memory Is Induced By Pkc Activation On Days Before Associative Learning, D. L. Alkon, H. Epstein, A. Kuzirian, M. C. Bennett, T. J. Nelson

Faculty & Staff Scholarship

Protein synthesis has long been known to be required for associative learning to consolidate into long-term memory. Here we demonstrate that PKC isozyme activation on days before training can induce the synthesis of proteins necessary and sufficient for subsequent long-term memory consolidation. Bryostatin (Bryo), a macrolide lactone with efficacy in subnanomolar concentrations and a potential therapeutic for Alzheimer's disease, is a potent activator of PKC, some of whose isozymes undergo prolonged activation after associative learning. Under normal conditions, two training events with paired visual and vestibular stimuli cause short-term memory of the mollusc Hermissenda that lasts ≈7 min. However, after …

Arachidonic Acid Inhibits The Insulin Induction Of Glucose-6-Phosphate Dehydrogenase Via P38 Map Kinase, Indrani Talukdar, Wioletta Szeszel-Fedorowicz, Lisa M. Salati

Faculty & Staff Scholarship

No abstract provided.

Palm Is Expressed In Both Developing And Adult Mouse Lens And Retina., Meryl Castellini, Louise V Wolf, Bharesh K Chauhan, Deni S Galileo, Manfred W Kilimann, Ales Cvekl, Melinda K Duncan

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Paralemmin (Palm) is a prenyl-palmitoyl anchored membrane protein that can drive membrane and process formation in neurons. Earlier studies have shown brain preferred Palm expression, although this protein is a major water insoluble protein in chicken lens fiber cells and the Palm gene may be regulated by Pax6. METHODS: The expression profile of Palm protein in the embryonic, newborn and adult mouse eye as well as dissociated retinal neurons was determined by confocal immunofluorescence. The relative mRNA levels of Palm, Palmdelphin (PalmD) and paralemmin2 (Palm2) in the lens and retina were determined by real time rt-PCR. RESULTS: In the …

Rna Polymerase Ii Synthesizes Antisense Rna In Plasmodium Falciparum, Kevin T. Militello, Vishal Patel, Anne-Danielle Chessler, Julia K. Fisher, Jacob M. Kasper, Anusha Gunasekera, Dyann F. Wirth

Biology

The recent identification of antisense RNA in the transcriptomes of many eukaryotes has generated enormous interest. The presence of antisense RNA in Plasmodium falciparum, the causative agent of severe malaria, remains controversial. Elucidation of the mechanism of antisense RNA in P. falciparum synthesis is critical in order to demonstrate the origin and function of these transcripts. Therefore, a systematic analysis of antisense and sense RNA synthesis was performed using direct labeling experiments. Nuclear run on experiments with single-stranded DNA probes demonstrated that antisense RNA is synthesized in the nucleus at several genomic loci. Antisense RNA synthesis is sensitive to the …

The Chemistry Of My Affections, David Scott Smith

LSU Master's Theses

Although I have always been interested in the origins of my thought processes and the methods and compulsions that motivate my work, in past work I have avoided self portraiture, or blatant explorations into my own sense of self. With my thesis project I wanted to conduct an express exploration into the psychology of my motivations. My initial goal was to create an environment, a sense of place, where both the viewer and myself are drawn into the work, and confronted with a unique experience of personal expression. The focal point is a bath enclosed within a grotto, which symbolizes …

Cdc42 Regulates Arsenic-Induced Nadph Oxidase Activation And Cell Migration Through Actin Filament Reorganization, Yong Qian, Ke Jian Liu, Yan Chen, Daniel C. Flynn, Vince Castranova, Xianglin Shi

Faculty & Staff Scholarship

No abstract provided.

Crystal Structure Of The Gtpase Domain Of Rat Dynamin 1, Thomas F. Reubold, Susanne Eschenburg, Andreas Becker, Marilyn Leonard, Sandra L. Schmid, Richard B. Vallee, F. Jon Kull, Dietmar J. Manstein

Dartmouth Scholarship

Here, we present the 1.9-A crystal structure of the nucleotide-free GTPase domain of dynamin 1 from Rattus norvegicus. The structure corresponds to an extended form of the canonical GTPase fold observed in Ras proteins. Both nucleotide-binding switch motifs are well resolved, adopting conformations that closely resemble a GTP-bound state not previously observed for nucleotide-free GTPases. Two highly conserved arginines, Arg-66 and Arg-67, greatly restrict the mobility of switch I and are ideally positioned to relay information about the nucleotide state to other parts of the protein. Our results support a model in which switch I residue Arg-59 gates GTP binding …

Silencing Of Retrotransposons In Dictyostelium By Dna Methylation And Rnai, Markus Kuhlmann, Branimira E. Borisova, Markus Kaller, Pontus Larsson, Dirk Stach, Jianbo Na, Ludwig Eichinger, Frank Lyko, Victor Ambros, Fredrik Soderbom, Christian Hammann, Wolfgang Nellen

Dartmouth Scholarship

We have identified a DNA methyltransferase of the Dnmt2 family in Dictyostelium that was denominated DnmA. Expression of the dnmA gene is downregulated during the developmental cycle. Overall DNA methylation in Dictyostelium is ∼0.2% of the cytosine residues, which indicates its restriction to a limited set of genomic loci. Bisulfite sequencing of specific sites revealed that DnmA is responsible for methylation of mostly asymmetric C-residues in the retrotransposons DIRS-1 and Skipper. Disruption of the gene resulted in a loss of methylation and in increased transcription and mobilization of Skipper. Skipper transcription was also upregulated in strains that had genes encoding …

Global Gene Expression Profiling Of Cells Overexpressing Smc3., Giancarlo Ghiselli, Chang-Gong Liu

Department of Microbiology and Immunology Faculty Papers

BACKGROUND: The Structural Maintenance of Chromosome 3 protein (SMC3) plays an essential role during the sister chromatid separation, is involved in DNA repair and recombination and participates in microtubule-mediated intracellular transport. SMC3 is frequently elevated in human colon carcinoma and overexpression of the protein transforms murine NIH3T3 fibroblasts. In order to gain insight into the mechanism of SMC3-mediated tumorigenesis a gene expression profiling was performed on human 293 cells line stably overexpressing SMC3. RESULTS: Biotinylated complementary RNA (cRNA) was used for hybridization of a cDNAmicroarray chip harboring 18,861 65-mer oligos derived from the published dEST sequences. After filtering, the hybridization …

Mitochondrial Dna Mutations, Apoptosis, And The Misfolded Protein Response., Justin L. Mott, Dekui Zhang, Hans Peter Zassenhaus

Journal Articles: Biochemistry & Molecular Biology

Studies of transgenic mice with accelerated accumulation of mtDNA mutations specifically in the heart lead us to propose that apoptotic signaling and cell death is central to the pathogenesis of mtDNA mutations in aging. It is the cellular response to that apoptotic signaling and the organ?s compensatory response to a loss of cells that specify the phenotype of an accumulation of mtDNA mutations. In the heart, cardiomyocytes induce a vigorous anti-apoptotic, pro-survival response to counteract mitochondrial apoptotic signaling. The heart up-regulates contractility of remaining myocytes in order to maintain cardiac output. We hypothesize that mutant mitochondrial proteins originate apoptotic signaling …

Mechanistic Differences In Rna-Dependent Dna Polymerization And Fidelity Between Murine Leukemia Virus And Hiv-1 Reverse Transcriptases, Mark Skasko, Kellie K. Weiss, Holly M. Reynolds, Varuni Jamburuthugoda, Kwi Lee, Baek Kim

Biology

We compared the mechanistic and kinetic properties of murine leukemia virus (MuLV) and human immunodeficiency virus type 1 (HIV-1) reverse transcriptases (RTs) during RNA-dependent DNA polymerization and mutation synthesis using pre-steady-state kinetic analysis. First, MuLV RT showed 6.5-121.6-fold lower binding affinity (Kd) to deoxynucleotide triphosphate (dNTP) substrates than HIV-1 RT, although the two RTs have similar incorporation rates (kpol). Second, compared with HIV-1 RT, MuLV RT showed dramatic reduction during multiple dNTP incorporations at low dNTP concentrations. Presumably, due to its low dNTP binding affinity, the dNTP binding step becomes rate-limiting in the multiple rounds of the dNTP incorporation by …

Ccl20/Macrophage Inflammatory Protein 3Α And Tumor Necrosis Factor Alpha Production By Primary Uterine Epithelial Cells In Response To Treatment With Lipopolysaccharide Or Pam3cys, M. A. Crane-Godreau, C. R. Wira

Dartmouth Scholarship

Having previously shown that CCL20/macrophage inflammatory protein 3 and tumor necrosis factor alpha (TNF-alpha) are released by polarized primary rat uterine epithelial cells (UEC) in response to Escherichia coli but not to Lactobacillus rhamnosus , we sought to determine if epithelial cells are responsive to pathogen-associated molecular patterns (PAMP), including lipopolysaccharide (LPS), lipoteichoic acid (LTA), and Pam 3 Cys, a bacterial lipoprotein analog. Epithelial cells were grown to confluence on Nunc cell culture inserts prior to apical treatment with PAMPs. In response to LPS, LTA, and Pam 3 Cys (EMC Microcollection GmbH, Tu ̈- bingen, Germany), CCL20 levels increased (4- …

Inhibition Modifies The Effects Of Slow Calcium-Activated Potassium Channels On Epileptiform Activity In A Neuronal Network Model, Keun-Hang Susan Yang, Piotr J. Franaszczuk, Gregory K. Bergey

Mathematics, Physics, and Computer Science Faculty Articles and Research

Generation of epileptiform activity typically results from a change in the balance between network excitation and inhibition. Experimental evidence indicates that alterations of either synaptic activity or intrinsic membrane properties can produce increased network excitation. The slow Ca2+-activated K+ currents (sI AHP) are important modulators of neuronal firing rate and excitability and have important established and potential roles in epileptogenesis. While the effects of changes in sI AHP on individual neuronal excitability are readily studied and well established, the effects of such changes on network behavior are less well known. The experiments here utilize a defined small network model of …

Genetic Networks Controlling Retinal Injury, Felix R Vazquez-Chona, Amna N Khan, Chun K Chan, Anthony N Moore, Pramod K Dash, M Rosario Hernandez, Lu Lu, Elissa J Chesler, Kenneth F Manly, Robert W Williams, Eldon E Geisert

Faculty, Staff and Student Publications

PURPOSE: The present study defines genomic loci underlying coordinate changes in gene expression following retinal injury.

METHODS: A group of acute phase genes expressed in diverse nervous system tissues was defined by combining microarray results from injury studies from rat retina, brain, and spinal cord. Genomic loci regulating the brain expression of acute phase genes were identified using a panel of BXD recombinant inbred (RI) mouse strains. Candidate upstream regulators within a locus were defined using single nucleotide polymorphism databases and promoter motif databases.

RESULTS: The acute phase response of rat retina, brain, and spinal cord was dominated by transcription …

Prime-Boost Vaccination With Plasmid And Adenovirus Gene Vaccines Control Her2/Neu+ Metastatic Breast Cancer In Mice, Xiaoyan Wang, Jian-Ping Wang, Xiao-Mei Rao, Janet E Price, Heshan S Zhou, Lawrence B Lachman

Faculty, Staff and Student Publications

INTRODUCTION: Once metastasis has occurred, the possibility of completely curing breast cancer is unlikely, particularly for the 30 to 40% of cancers overexpressing the gene for HER2/neu. A vaccine targeting p185, the protein product of the HER2/neu gene, could have therapeutic application by controlling the growth and metastasis of highly aggressive HER2/neu+ cells. The purpose of this study was to determine the effectiveness of two gene vaccines targeting HER2/neu in preventive and therapeutic tumor models.

METHODS: The mouse breast cancer cell line A2L2, which expresses the gene for rat HER2/neu and hence p185, was injected into the mammary fat pad …

The Use Of Time-Resolved Fluorescence Imaging In The Study Of Protein Kinase C Localisation In Cells., Christopher D Stubbs, Stanley W Botchway, Simon J Slater, Anthony W Parker

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Two-photon-excitation fluorescence lifetime imaging (2P-FLIM) was used to investigate the association of protein kinase C alpha (PKCalpha) with caveolin in CHO cells. PKCalpha is found widely in the cytoplasm and nucleus in most cells. Upon activation, as a result of increased intracellular Ca2+ and production of DAG, through G-protein coupled-phospholipase C signalling, PKC translocates to a variety of regions in the cell where it phosphorylates and interacts with many signalling pathways. Due to its wide distribution, discerning a particular interaction from others within the cell is extremely difficult. RESULTS: Fluorescence energy transfer (FRET), between GFP-PKCalpha and DsRed-caveolin, was used …

Tsc2 Modulates Actin Cytoskeleton And Focal Adhesion Through Tsc1-Binding Domain And The Rac1 Gtpase, Elena Goncharova, Dmitry Goncharov, Daniel J. Noonan, Vera P Krymskaya

Molecular and Cellular Biochemistry Faculty Publications

Tuberous sclerosis complex (TSC) 1 and TSC2 are thought to be involved in protein translational regulation and cell growth, and loss of their function is a cause of TSC and lymphangioleiomyomatosis (LAM). However, TSC1 also activates Rho and regulates cell adhesion. We found that TSC2 modulates actin dynamics and cell adhesion and the TSC1-binding domain (TSC2-HBD) is essential for this function of TSC2. Expression of TSC2 or TSC2-HBD in TSC2-/- cells promoted Rac1 activation, inhibition of Rho, stress fiber disassembly, and focal adhesion remodeling. The down-regulation of TSC1 with TSC1 siRNA in TSC2-/- cells activated Rac1 and induced loss of …

The Kidney-Specific Wnk1 Isoform Is Induced By Aldosterone And Stimulates Epithelial Sodium Channel-Mediated Na+ Transport, Anikó Naray-Fejes-Toth, Peter M. Snyder, Géza Fejes-Toth

Dartmouth Scholarship

WNK1 belongs to a unique family of Ser/Thr kinases that have been implicated in the control of blood pressure. Intronic deletions in the WNK1 gene result in its overexpression and lead to pseudohypoaldosteronism type II, a disease with salt-sensitive hypertension and hyperkalemia. How overexpression of WNK1 leads to Na⁺ retention and hypertension is not entirely clear. Similarly, there is no information on the hormonal regulation of expression of WNK kinases. There are two main WNK1 transcripts expressed in the kidney: the originally described “long” WNK1 and a shorter transcript that is specifically expressed in the kidney (KS-WNK1). The goal …

Regulatory Role Of Glycogen Synthase Kinase 3 For Transcriptional Activity Of Add1/Srebp1c, Kang Ho Kim, Min Jeong Song, Eung Jae Yoo, Sung Sik Choe, Sang Dai Park, Jae Bum Kim

Faculty, Staff and Student Publications

Adipocyte determination- and differentiation-dependent factor 1 (ADD1) plays important roles in lipid metabolism and insulin-dependent gene expression. Because insulin stimulates carbohydrate and lipid synthesis, it would be important to decipher how the transcriptional activity of ADD1/SREBP1c is regulated in the insulin signaling pathway. In this study, we demonstrated that glycogen synthase kinase (GSK)-3 negatively regulates the transcriptional activity of ADD1/SREBP1c. GSK3 inhibitors enhanced a transcriptional activity of ADD1/SREBP1c and expression of ADD1/SREBP1c target genes including fatty acid synthase (FAS), acetyl-CoA carboxylase 1 (ACC1), and steroyl-CoA desaturase 1 (SCD1) in adipocytes and hepatocytes. In contrast, overexpression of GSK3beta down-regulated the transcriptional …

An Intramolecular Association Between Two Domains Of The Protein Kinase Fused Is Necessary For Hedgehog Signaling, Manuel Ascano Jr., David J. Robbins

Dartmouth Scholarship

The protein kinase Fused (Fu) is an integral member of the Hedgehog (Hh) signaling pathway. Although genetic studies demonstrate that Fu is required for the regulation of the Hh pathway, the mechanistic role that it plays remains largely unknown. Given our difficulty in developing an in vitro kinase assay for Fu, we reasoned that the catalytic activity of Fu might be highly regulated. Several mechanisms are known to regulate protein kinases, including self-association in either an intra- or an intermolecular fashion. Here, we provide evidence that Hh regulates Fu through intramolecular association between its kinase domain (ΔFu) and its carboxyl-terminal …

Characterization Of The Chicken Inward Rectifier K+ Channel Irk1/Kir2.1 Gene., Hideki Mutai, Lawrence C Kenyon, Emily Locke, Nami Kikuchi, John Carl Oberholtzer

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Inward rectifier potassium channels (IRK) contribute to the normal function of skeletal and cardiac muscle cells. The chick inward rectifier K+ channel cIRK1/Kir2.1 is expressed in skeletal muscle, heart, brain, but not in liver; a distribution similar but not identical to that of mouse Kir2.1. We set out to explore regulatory domains of the cIRK1 promoter that enhance or inhibit expression of the gene in different cell types. RESULTS: We cloned and characterized the 5'-flanking region of cIRK1. cIRK1 contains two exons with splice sites in the 5'-untranslated region, a structure similar to mouse and human orthologs. cIRK1 has …

Drosophila Rnase Z Processes Mitochondrial And Nuclear Pre-Trna 3′ Ends In Vivo, Edward B. Dubrovsky, Veronica A. Dubrovskaya, Louis Levinger, Steffen Schiffer, Anita Marchfelder

Dartmouth Scholarship

Although correct tRNA 3′ ends are crucial for protein biosynthesis, generation of mature tRNA 3′ ends in eukaryotes is poorly understood and has so far only been investigated in vitro. We report here for the first time that eukaryotic tRNA 3′ end maturation is catalysed by the endonuclease RNase Z in vivo. Silencing of the JhI‐1 gene (RNase Z homolog) in vivo with RNAi in Drosophila S2 cultured cells causes accumulation of nuclear and mitochondrial pre‐tRNAs, suggesting that JhI‐1 encodes both forms of the tRNA 3′ endonuclease RNase Z, and establishing its biological role in endonucleolytic tRNA 3′ …

Two Drosophila Suppressors Of Cytokine Signaling (Socs) Differentially Regulate Jak And Egfr Pathway Activities, Jason S. Rawlings, Gabriela Rennebeck, Susan M.W. Harrison, Rongwen Xi, Douglas A. Harrison

Biology Faculty Publications

BACKGROUND: The Janus kinase (JAK) cascade is an essential and well-conserved pathway required to transduce signals for a variety of ligands in both vertebrates and invertebrates. While activation of the pathway is essential to many processes, mutations from mammals and Drosophila demonstrate that regulation is also critical. The SOCS (Suppressor Of Cytokine Signaling) proteins in mammals are regulators of the JAK pathway that participate in a negative feedback loop, as they are transcriptionally activated by JAK signaling. Examination of one Drosophila SOCS homologue, Socs36E, demonstrated that its expression is responsive to JAK pathway activity and it is capable of downregulating …

Phylogenetic Analysis Of The Formin Homology 2 Domain, Henry N. Higgs, Kevin J. Peterson

Dartmouth Scholarship

Formin proteins are key regulators of eukaryotic actin filament assembly and elongation, and many species possess multiple formin isoforms. A nomenclature system based on fundamental features would be desirable, to aid the rapid identification and characterization of novel formins. In this article, we attempt to systematize the formin family by performing phylogenetic analyses of the formin homology 2 (FH2) domain, an independently folding region common to all formins, which alone can influence actin dynamics. Through database searches, we identify 101 FH2 domains from 26 eukaryotic species, including 15 in mice. Sequence alignments reveal a highly conserved yeast-specific insert in the …

A Subset Of Liver Nk T Cells Is Activated During Leishmania Donovani Infection By Cd1d-Bound Lipophosphoglycan, Joseph L. Amprey, Jin S. Im, Salvatore J. Turco, Henry W. Murray, Petr A. Illarionov, Gurdyal S. Besra, Steven A. Porcelli, Gerald F. Späth

Molecular and Cellular Biochemistry Faculty Publications

Natural killer (NK) T cells are activated by synthetic or self-glycolipids and implicated in innate host resistance to a range of viral, bacterial, and protozoan pathogens. Despite the immunogenicity of microbial lipoglycans and their promiscuous binding to CD1d, no pathogen-derived glycolipid antigen presented by this pathway has been identified to date. In the current work, we show increased susceptibility of NK T cell–deficient CD1d^−/− mice to Leishmania donovani infection and Leishmania-induced CD1d-dependent activation of NK T cells in wild-type animals. The elicited response was Th1 polarized, occurred as early as 2 h after infection, and was independent from …

Multiple Mechanisms Regulate Numa Dynamics At Spindle Poles, Olga Kisurina-Evgenieva, Gary Mack, Quansheng Du, Ian Macara, Alexey Khodjakov, Duane A. Compton

Dartmouth Scholarship

The large coiled-coil protein NuMA plays an essential role in organizing microtubule minus ends at spindle poles in vertebrate cells. Here, we use both in vivo and in vitro methods to examine NuMA dynamics at mitotic spindle poles. Using fluorescence recovery after photobleaching, we show that an exogenously expressed green-fluorescent-protein/NuMA fusion undergoes continuous exchange between soluble and spindle-associated pools in living cells. These dynamics require cellular energy and display an average half-time for fluorescence recovery of approximately 3 minutes. To explore how NuMA dynamics at spindle poles is regulated, we exploited the association of NuMA with microtubule asters formed in …

Heme Oxygenase-2 Gene Deletion Attenuates Oxidative Stress In Neurons Exposed To Extracellular Hemin., Raymond F Regan, Jing Chen, Luna Benvenisti-Zarom

Department of Emergency Medicine Faculty Papers

BACKGROUND: Hemin, the oxidized form of heme, accumulates in intracranial hematomas and is a potent oxidant. Growing evidence suggests that it contributes to delayed injury to surrounding tissue, and that this process is affected by the heme oxygenase enzymes. In a prior study, heme oxygenase-2 gene deletion increased the vulnerability of cultured cortical astrocytes to hemin. The present study tested the effect of HO-2 gene deletion on protein oxidation, reactive oxygen species formation, and cell viability after mixed cortical neuron/astrocyte cultures were incubated with neurotoxic concentrations of hemin. RESULTS: Continuous exposure of wild-type cultures to 1-10 microM hemin for 14 …

Nf-Kappab And Ap-1 Connection: Mechanism Of Nf-Kappab-Dependent Regulation Of Ap-1 Activity, Shuichi Fujioka, Jiangong Niu, Christian Schmidt, Guido M Sclabas, Bailu Peng, Tadashi Uwagawa, Zhongkui Li, Douglas B Evans, James L Abbruzzese, Paul J Chiao

Faculty, Staff and Student Publications

Nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1) transcription factors regulate many important biological and pathological processes. Activation of NF-kappaB is regulated by the inducible phosphorylation of NF-kappaB inhibitor IkappaB by IkappaB kinase. In contrast, Fos, a key component of AP-1, is primarily transcriptionally regulated by serum responsive factors (SRFs) and ternary complex factors (TCFs). Despite these different regulatory mechanisms, there is an intriguing possibility that NF-kappaB and AP-1 may modulate each other, thus expanding the scope of these two rapidly inducible transcription factors. To determine whether NF-kappaB activity is involved in the regulation of fos expression in response …

Binding Between The Niemann–Pick C1 Protein And A Photoactivatable Cholesterol Analog Requires A Functional Sterol-Sensing Domain, Nobutaka Ohgami, Dennis C. Ko, Matthew Thomas, Matthew P. Scott, Catherine C. Y. Chang, Ta-Yuan Chang

Dartmouth Scholarship

Niemann-Pick type C (NPC) 1 protein plays important roles in moving cholesterol and other lipids out of late endosomes by means of vesicular trafficking, but it is not known whether NPC1 directly interacts with cholesterol. We performed photoaffinity labeling of intact cells expressing fluorescent protein (FP)-tagged NPC1 by using [(3)H]7,7-azocholestanol ([(3)H]AC). After immunoprecipitation, (3)H-labeled NPC1-GFP appeared as a single band. Including excess unlabeled sterol to the labeling reaction significantly diminished the labeling. Altering the NPC1 sterol-sensing domain (SSD) with loss-of-function mutations (P692S and Y635C) severely reduced the extent of labeling. To further demonstrate the specificity of labeling, we show that …

The Caenorhabditis Elegans F-Box Protein Sel-10 Promotes Female Development And May Target Fem-1 And Fem-3 For Degradation By The Proteasome, Sibylle Jager, Hillel T. Schwartz, H. Robert Horvitz, Barbara Conradt

Dartmouth Scholarship

The Caenorhabditis elegans F-box protein SEL-10 and its human homolog have been proposed to regulate LIN-12 Notch signaling by targeting for ubiquitin-mediated proteasomal degradation LIN-12 Notch proteins and SEL-12 PS1 presenilins, the latter of which have been implicated in Alzheimer's disease. We found that sel-10 is the same gene as egl-41, which previously had been defined by gain-of-function mutations that semidominantly cause masculinization of the hermaphrodite soma. Our results demonstrate that mutations causing loss-of-function of sel-10 also have masculinizing activity, indicating that sel-10 functions to promote female development. Genetically, sel-10 acts upstream of the genes fem-1, fem-2, and fem-3 and …