Cell Biology Commons^™

Effects Of A Systemic High Urea Concentration On The Endometrial And Embryonic Transcriptomes Of The Mare, Yatta Linhares Boakari

Theses and Dissertations--Veterinary Science

Pregnancy loss remains a major source of economic cost to the equine industry. Frequently, the exact causes of pregnancy loss remain unknown. It has been shown, in other species, that increased dietary protein leading to elevated blood urea nitrogen concentrations (BUN) can be a factor in decreased survival of the early embryo. Our studies provided novel information regarding the effects of elevated BUN on endometrium and embryos from mares as well as insights on changes in their gene expression. Our first objective was to develop an experimental model to elevate BUN during diestrus using intravenous urea infusion. We analyzed the …

Mutations Of Fus Cause Aggregation Of Rna Binding Proteins, Disruptions In Protein Synthesis, And Dysregulation Of Nonsense Mediated Decay, Marisa Elizabeth Kamelgarn

Theses and Dissertations--Toxicology and Cancer Biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron death and subsequent muscle atrophy. Approximately 15% of ALS cases are inheritable, and mutations in the Fused in Sarcoma (FUS) gene contribute to approximately 5% of these cases, as well as about 2% of sporadic cases. FUS performs a diverse set of cellular functions, including being a major regulator of RNA metabolism. FUS undergoes liquid- liquid phase transition in vitro, allowing for its participation in stress granules and RNA transport granules. Phase transition also contributes to the formation of cytoplasmic inclusions found in the …

The Effects Of A Ketone Body On Synaptic Transmission, Alexandra Elizabeth Stanback

Theses and Dissertations--Biology

The ketogenic diet is commonly used to control epilepsy, especially in cases when medications cannot. The diet typically consists of high fat, low carb, and adequate protein and produces a metabolite called acetoacetate. Seizure activity is characterized by glutamate excitotoxicity and therefore glutamate regulation is a point of research for control of these disorders. Acetoacetate is heavily implicated as the primary molecule responsible for decreasing glutamate in the synapse; it is believed that acetoacetate interferes with the transport of glutamate into the synaptic vesicles. The effects on synaptic transmission at glutamatergic synapses was studied in relation to the ketogenic diet …

Data On Spectrum-Based Fluorescence Resonance Energy Transfer Measurement Of E. Coli Multidrug Transporter Acrb, Yuguang Cai, Thomas E. Wilkop, Yinan Wei

Chemistry Faculty Publications

This paper presented the dataset of correction parameters used in the determination of the energy transfer efficiencies from the spectrum-based fluorescence resonance energy transfer (FRET) measurement in a trimeric membrane protein AcrB. The cyan fluorescent protein (CFP) and yellow fluorescent protein (YPet) were used as the donor and acceptor, respectively. Two AcrB fusion proteins were constructed, AcrB-CFP and AcrB-YPet. The proteins were co-expressed in Escherichia coli cells, and energy transfer efficiency were determined in live cells. To obtain reliable energy transfer data, a complete set of correction parameters need to be first determined to accommodate for factors such as background …

Double-Stranded Rna Binding Protein, Staufen, Is Required For The Initiation Of Rnai In Coleopteran Insects, June-Sun Yoon, Kanakachari Mogilicherla, Dhandapani Gurusamy, Xien Chen, Shankar C. R. R. Chereddy, Subba R. Palli

Entomology Faculty Publications

RNA interference (RNAi) is being used to develop methods to control pests and disease vectors. RNAi is robust and systemic in coleopteran insects but is quite variable in other insects. The determinants of efficient RNAi in coleopterans, as well as its potential mechanisms of resistance, are not known. RNAi screen identified a double-stranded RNA binding protein (StaufenC) as a major player in RNAi. StaufenC homologs have been identified in only coleopteran insects. Experiments in two coleopteran insects, Leptinotarsa decemlineata and Tribolium castaneum, showed the requirement of StaufenC for RNAi, especially for processing of double-stranded RNA (dsRNA) to small interfering …

Assembly-Hub Function Of Er-Localized Snare Proteins In Biogenesis Of Tombusvirus Replication Compartment, Zsuzsanna Sasvari, Nikolay Kovalev, Paulina Alatriste Gonzalez, Kai Xu, Peter D. Nagy

Plant Pathology Faculty Publications

Positive-strand RNA viruses assemble numerous membrane-bound viral replicase complexes within large replication compartments to support their replication in infected cells. Yet the detailed mechanism of how given subcellular compartments are subverted by viruses is incompletely understood. Although, Tomato bushy stunt virus (TBSV) uses peroxisomal membranes for replication, in this paper, we show evidence that the ER-resident SNARE (soluble NSF attachment protein receptor) proteins play critical roles in the formation of active replicase complexes in yeast model host and in plants. Depletion of the syntaxin 18-like Ufe1 and Use1, which are components of the ER SNARE complex in the ERAS (ER …

Multivariate Analysis To Identify Potential Biomarkers For Prognosis And Treatment Resistance In Head And Neck Cancer Patients, Christina Ann Wicker

Theses and Dissertations--Toxicology and Cancer Biology

It is estimated that nearly 50,000 individuals in the United States will be diagnosed with head and neck cancer in 2017 (American Cancer Society www.cancer.org). Ninety percent of oral cancers are head and neck squamous cell carcinoma (HNSCC). Major obstacles in the treatment of HNSCC are recurrence and treatment resistance, which contributes to increased mortality. Therefore, there is increased need to determine genetic alterations in HNSCC that may be ideal novel drug targets, and biomarkers to improve diagnostic and prognostic testing.

Abnormal localization and overexpression of base excision repair protein and transcriptional regulator Apurinic/Apyrimidic endonuclease (APE1) has been associated with …

Jak/Stat Signaling Regulates Gametogenesis And Age-Related Reproductive Maintenance, Michelle Suzanne Giedt

Theses and Dissertations--Biology

Cell signaling is central to integration of internal and external cues that regulate development and homeostasis. Most development is thought of as pre-adult, but limited developmental processes occur in adults. Gametogenesis incorporates elements of both these facets, with a distinct developmental plan for gamete synthesis which is regulated by integration of homeostatic inputs such as nutrient status, and environmental cues. Signaling pathways integrate and transduce information from these cues to evoke a response. A decline in homeostasis and subsequent cues occurs over time, in the case of reproductive tissues leading to a progressive loss of fertility. The Janus Kinase and …

Controlling Platelet Secretion To Modulate Hemostasis And Thrombosis, Smita Joshi

Theses and Dissertations--Molecular and Cellular Biochemistry

Upon vascular injury, activated blood platelets fuse their granules to the plasma membrane and release cargo to regulate the vascular microenvironment, a dynamic process central to platelet function in many critical processes including hemostasis, thrombosis, immunity, wound healing, angiogenesis etc. This granule- plasma membrane fusion is mediated by a family of membrane proteins- Soluble N-ethyl maleimide Attachment Receptor Proteins(SNAREs). SNAREs that reside on vesicle (v-SNAREs) /Vesicle-Associated Membrane Proteins(VAMPs) interact with target/t-SNAREs forming a trans-bilayer complex that facilitates granule fusion. Though many components of exocytic machinery are identified, it is still not clear how it could be manipulated to prevent …

Elucidating The Role Of Nidogen In The Fusion Of The Choroid Fissure, Nicholas W. Carrara

Theses and Dissertations--Biology

In the developing embryo, the timely fusion of opposing epithelial sheets into one uniform layer denotes the completion of several developmental events. Failure of this epithelial sheet fusion event (ESF) within the choroid fissure (CF) is associated with the congenital disorder Ocular Coloboma, and is one of the leading causes of pediatric blindness. A requirement for a highly coordinated dismantling of the basement membrane (BM) to allow for fusion to occur is undoubted, however the underlying mechanisms of this process are poorly understood. Due to its BM crosslinking capabilities, I have hypothesized that the regulation of nidogen plays a crucial …

An Optimized Solid-Phase Reduction And Capture Strategy For The Study Of Reversibly-Oxidized Cysteines And Its Application To Metal Toxicity, John Andrew Hitron

Theses and Dissertations--Toxicology and Cancer Biology

The reversible oxidation of cysteine by reactive oxygen species (ROS) is both a mechanism for cellular protein signaling as well as a cause of cellular injury and death through the generation of oxidative stress. The study of cysteine oxidation is complicated by the methodology currently available to isolate and enrich oxidized-cysteine containing proteins. We sought to simplify this process by reducing the time needed to process samples and reducing sample loss and contamination risk.

We accomplished this by eliminating precipitation steps needed for the protocol by (a) introducing an in-solution NEM-quenching step prior to reduction and (b) replacing soluble dithiothreitol …

Applications Of Cell-Derived Vesicles: From Single Molecule Studies To Drug Delivery, Faruk H. Moonschi

Theses and Dissertations--Chemistry

Single molecule studies can provide information of biological molecules which otherwise is lost in ensemble studies. A wide variety of fluorescence-based techniques are utilized for single molecule studies. While these tools have been widely applied for imaging soluble proteins, single molecule studies of transmembrane proteins are much more complicated. A primary reason for this is that, unlike membrane proteins, soluble proteins can be easily isolated from the cellular environment. One approach to isolate membrane proteins into single molecule level involves a very low label expression of the protein in cells. However, cells generate background fluorescence leading to a very low …

The Role Of Talin2 In Breast Cancer Tumorigenesis And Metastasis, Liqing Li, Xiang Li, Lei Qi, Piotr G. Rychahou, Naser Jafari, Cai Huang

Markey Cancer Center Faculty Publications

Recent studies show that talin2 has a higher affinity to β-integrin tails and is indispensable for traction force generation and cell invasion. However, its roles in cell migration, cancer cell metastasis and tumorigenesis remain to be determined. Here, we used MDA-MB-231 human breast cancer cells as a model to define the roles of talin2 in cell migration, invasion, metastasis and tumorigenesis. We show here that talin2 knockdown (KD) inhibited cell migration and focal adhesion dynamics, a key step in cell migration, and that talin2 knockout (KO) inhibited cell invasion and traction force generation, the latter is crucial for cell invasion. …

Nanoparticle Delivery Of Mir-34a Eradicates Long-Term-Cultured Breast Cancer Stem Cells Via Targeting C22orf28 Directly, Xiaoti Lin, Weiyu Chen, Fengqin Wei, Binhua P. Zhou, Mien-Chie Hung, Xiaoming Xie

Molecular and Cellular Biochemistry Faculty Publications

Rationale: Cancer stem cells (CSCs) have been implicated as the seeds of therapeutic resistance and metastasis, due to their unique abilities of self-renew, wide differentiation potentials and resistance to most conventional therapies. It is a proactive strategy for cancer therapy to eradicate CSCs. Methods: Tumor tissue-derived breast CSCs (BCSC), including XM322 and XM607, were isolated by fluorescence-activated cell sorting (FACS); while cell line-derived BCSC, including MDA-MB-231.SC and MCF-7.SC, were purified by magnetic-activated cell sorting (MACS). Analyses of microRNA and mRNA expression array profiles were performed in multiple breast cell lines. The mentioned nanoparticles were constructed following the standard molecular cloning …

Stabilization Of The Transcription Factors Slug And Twist By The Deubiquitinase Dub3 Is A Key Requirement For Tumor Metastasis, Yiwei Lin, Yu Wang, Qing Shi, Qian Yu, Cuicui Liu, Jing Feng, Jiong Deng, B. Mark Evers, Binhua P. Zhou, Yadi Wu

Molecular and Cellular Biochemistry Faculty Publications

The Epithelial-mesenchymal transition (EMT) represents a cellular de-differentiation process that provides cells with the increased plasticity required during embryonic development, tissue remodeling, wound healing and metastasis. Slug and Twist are two key EMT transcription factors (EMT-TFs) that are tightly regulated via ubiquitination and degradation. How Slug and Twist escape degradation and become stabilized in cancer cells remains unclear. One plausible mechanism of Slug and Twist stabilization involves removal of ubiquitin by deubiquitinases (DUBs). In this study, we identified Dub3 as a novel DUB for both Slug and Twist. We further found that Dub3 overexpression increased Slug and Twist protein levels …

A Naturally Generated Decoy Of The Prostate Apoptosis Response-4 Protein Overcomes Therapy Resistance In Tumors, Nikhil Hebbar, Ravshan Burikhanov, Nidhi Shukla, Shirley Qiu, Yanming Zhao, Kojo S. J. Elenitoba-Johnson, Vivek M. Rangnekar

Radiation Medicine Faculty Publications

Primary tumors are often heterogeneous, composed of therapy-sensitive and emerging therapy-resistant cancer cells. Interestingly, treatment of therapy-sensitive tumors in heterogeneous tumor microenvironments results in apoptosis of therapy-resistant tumors. In this study, we identify a prostate apoptosis response-4 (Par-4) amino-terminal fragment (PAF) that is released by diverse therapy-sensitive cancer cells following therapy-induced caspase cleavage of the tumor suppressor Par-4 protein. PAF caused apoptosis in cancer cells resistant to therapy and inhibited tumor growth. A VASA segment of Par-4 mediated its binding and degradation by the ubiquitin ligase Fbxo45, resulting in loss of Par-4 proapoptotic function. Conversely, PAF, which contains this VASA …

Reversion Of Epithelial-Mesenchymal Transition By A Novel Agent Dz-50 Via Igf Binding Protein-3 In Prostate Cancer Cells, Zheng Cao, Shahriar Koochekpour, Stephen E. Strup, Natasha Kyprianou

Urology Faculty Publications

Dysregulation of transforming growth factor-β1 (TGF-β1) and insulin-like growth factor (IGF) axis has been linked to reactive stroma dynamics in prostate cancer progression. IGF binding protein-3 (IGFBP3) induction is initiated by stroma remodeling and could represent a potential therapeutic target for prostate cancer. In previous studies a lead quinazoline-based Doxazosin® derivative, DZ-50, impaired prostate tumor growth by targeting proteins involved in focal adhesion, anoikis resistance and epithelial-mesenchymal-transition (EMT). This study demonstrates that DZ-50 increased expression of the epithelial marker E-cadherin, and decreased the mesenchymal marker N-cadherin in human prostate cancer cells. In DU-145 cells, the effect of DZ-50 on EMT …

The Regulation Of Snail: On The Ubiquitin Edge, Qian Yu, Binhua P. Zhou, Yadi Wu

Pharmacology and Nutritional Sciences Faculty Publications

Metastasis accounts for a majority of cancer death. One key feature during metastasis is epithelial-mesenchymal transition (EMT), which is regulated by transcription factors such as Snail and Twist. In non-malignant cells, Snail has a short half-life and is degraded via ubiquitination, but its stability is increased in cancer cell. However, the mechanism by which Snail escapes ubiquitination and degradation remains unknown. Recently, we found that Dub3 is a deubiquinase of Snail. Most importantly, we determined that Dub3 responded to extracellular signals such as IL-6, and that the resultant signaling prevented Snail degradation, and promoted cancer growth, invasion, and migration. In …

Macrophages Are Necessary For Epimorphic Regeneration In African Spiny Mice, Jennifer Simkin, Thomas R. Gawriluk, John C. Gensel, Ashley W. Seifert

Biology Faculty Publications

How the immune system affects tissue regeneration is not well understood. In this study, we used an emerging mammalian model of epimorphic regeneration, the African spiny mouse, to examine cell-based inflammation and tested the hypothesis that macrophages are necessary for regeneration. By directly comparing inflammatory cell activation in a 4 mm ear injury during regeneration (Acomys cahirinus) and scarring (Mus musculus), we found that both species exhibited an acute inflammatory response, with scarring characterized by stronger myeloperoxidase activity. In contrast, ROS production was stronger and more persistent during regeneration. By depleting macrophages during injury, we demonstrate …

Paracrine Regulation Of Melanocyte Genomic Stability: A Focus On Nucleotide Excision Repair, Stuart Gordon Jarrett, Katharine Marie Carter, John August D'Orazio

Markey Cancer Center Faculty Publications

UV radiation is a major environmental risk factor for the development of melanoma by causing DNA damage and mutations. Resistance to UV damage is largely determined by the capacity of melanocytes to respond to UV injury by repairing mutagenic photolesions. The nucleotide excision repair (NER) pathway is the major mechanism by which cells correct UV photodamage. This multistep process involves the basic steps of damage recognition, isolation, localized strand unwinding, assembly of a repair complex, excision of the damage‐containing strand 3′ and 5′ to the photolesion, synthesis of a sequence‐appropriate replacement strand, and finally ligation to restore continuity of genomic …

Melatonin And Its Metabolites Protect Human Melanocytes Against Uvb-Induced Damage: Involvement Of Nrf2-Mediated Pathways, Zorica Janjetovic, Stuart G. Jarrett, Elizabeth F. Lee, Cory Duprey, Russel J. Reiter, Andrzej T. Slominski

Toxicology and Cancer Biology Faculty Publications

Ultraviolet light (UV) is an inducer of reactive oxygen species (ROS) as well as 6-4-photoproducts and cyclobutane pyrimidine dimers (CPD) in the skin, which further cause damage to the skin cells. Irradiation of cultured human melanocytes with UVB stimulated ROS production, which was reduced in cells treated with melatonin or its metabolites: 6-hydroxymelatonin (6-OHM), N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), N-acetylserotonin (NAS), and 5-methoxytryptamine (5-MT). Melatonin and its derivatives also stimulated the expression of NRF2 (nuclear factor erythroid 2 [NF-E2]-related factor 2) and its target enzymes and proteins that play an important role in cell protection from different damaging factors including UVB. Silencing …

Mechanotransduction Current Is Essential For Stability Of The Transducing Stereocilia In Mammalian Auditory Hair Cells, A. Catalina Vélez-Ortega, Mary J. Freeman, Artur A. Indzhykulian, Jonathan M. Grossheim, Gregory I. Frolenkov

Physiology Faculty Publications

Mechanotransducer channels at the tips of sensory stereocilia of inner ear hair cells are gated by the tension of 'tip links' interconnecting stereocilia. To ensure maximal sensitivity, tip links are tensioned at rest, resulting in a continuous influx of Ca²⁺ into the cell. Here we show that this constitutive Ca²⁺ influx, usually considered as potentially deleterious for hair cells, is in fact essential for stereocilia stability. In the auditory hair cells of young postnatal mice and rats, a reduction in mechanotransducer current, via pharmacological channel blockers or disruption of tip links, leads to stereocilia shape changes and shortening. …

Relb Expression Determines The Differential Effects Of Ascorbic Acid In Normal And Cancer Cells, Xiaowei Wei, Yong Xu, Fang Fang Xu, Luksana Chaiswing, David M. Schnell, Teresa Noel, Chi Wang, Jinfei Chen, Daret K. St. Clair, William H. St. Clair

Toxicology and Cancer Biology Faculty Publications

Cancer cells typically experience higher oxidative stress than normal cells, such that elevating pro-oxidant levels can trigger cancer cell death. Although pre-exposure to mild oxidative agents will sensitize cancer cells to radiation, this pre-exposure may also activate the adaptive stress defense system in normal cells. Ascorbic acid is a prototype redox modulator that when infused intravenously appears to kill cancers without injury to normal tissues; however, the mechanisms involved remain elusive. In this study, we show how ascorbic acid kills cancer cells and sensitizes prostate cancer to radiation therapy while also conferring protection upon normal prostate epithelial cells against radiation-induced …

Dub3 Inhibition Suppresses Breast Cancer Invasion And Metastasis By Promoting Snail1 Degradation, Yadi Wu, Yu Wang, Yiwei Lin, Yajuan Liu, Yifan Wang, Jianhang Jia, Puja Singh, Young-In Chi, Chi Wang, Chenfang Dong, Wei Li, Min Tao, Dana L. Napier, Qiuying Shi, Jiong Deng, B. Mark Evers, Binhua P. Zhou

Pharmacology and Nutritional Sciences Faculty Publications

Snail1, a key transcription factor of epithelial–mesenchymal transition (EMT), is subjected to ubiquitination and degradation, but the mechanism by which Snail1 is stabilized in tumours remains unclear. We identify Dub3 as a bona fide Snail1 deubiquitinase, which interacts with and stabilizes Snail1. Dub3 is overexpressed in breast cancer; knockdown of Dub3 resulted in Snail1 destabilization, suppressed EMT and decreased tumour cell migration, invasion, and metastasis. These effects are rescued by ectopic Snail1 expression. IL-6 also stabilizes Snail1 by inducing Dub3 expression, the specific inhibitor WP1130 binds to Dub3 and inhibits the Dub3-mediating Snail1 stabilization in vitroand in vivo. …

Sumo Regulates The Activity Of Smoothened And Costal-2 In Drosophila Hedgehog Signaling, Jie Zhang, Yajuan Liu, Kai Jiang, Jianhang Jia

Markey Cancer Center Faculty Publications

In Hedgehog (Hh) signaling, the GPCR-family protein Smoothened (Smo) acts as a signal transducer that is regulated by phosphorylation and ubiquitination, which ultimately change the cell surface accumulation of Smo. However, it is not clear whether Smo is regulated by other post-translational modifications, such as sumoylation. Here, we demonstrate that knockdown of the small ubiquitin-related modifier (SUMO) pathway components Ubc9 (a SUMO-conjugating enzyme E2), PIAS (a SUMO-protein ligase E3), and Smt3 (the SUMO isoform in Drosophila) by RNAi prevents Smo accumulation and alters Smo activity in the wing. We further show that Hh-induced-sumoylation stabilizes Smo, whereas desumoylation by Ulp1 …

The Molecular Basis Of Talin2'S High Affinity Toward Β1-Integrin, Yaxia Yuan, Liqing Li, Yanyan Zhu, Lei Qi, Latifeh Azizi, Vesa P. Hytönen, Chang-Guo Zhan, Cai Huang

Molecular Modeling and Biopharmaceutical Center Faculty Publications

Talin interacts with β-integrin tails and actin to control integrin activation, thus regulating focal adhesion dynamics and cell migration. There are two talin genes, Tln1 and Tln2, which encode talin1 and talin2, and it is generally believed that talin2 functions redundantly with talin1. However, we show here that talin2 has a higher affinity to β1-integrin tails than talin1. Mutation of talin2 S339 to leucine, which can cause Fifth Finger Camptodactyly, a human genetic disease, completely disrupted its binding to β–integrin tails. Also, substitution of talin1 C336 with Ser enhanced the affinity of talin1, whereas substitution of talin2 S339 with …

Phlpp Regulates Hexokinase 2-Dependent Glucose Metabolism In Colon Cancer Cells, Xiaopeng Xiong, Yang-An Wen, Mihail I. Mitov, Mary C. Oaks, Shigeki Miyamoto, Tianyan Gao

Markey Cancer Center Faculty Publications

Increased glucose metabolism is considered as one of the most important metabolic alterations adapted by cancer cells in order to generate energy as well as high levels of glycolytic intermediates to support rapid proliferation. PH domain leucine-rich repeat protein phosphatase (PHLPP) belongs to a novel family of Ser/Thr protein phosphatases that function as tumor suppressors in various types of human cancer. Here we determined the role of PHLPP in regulating glucose metabolism in colon cancer cells. Knockdown of PHLPP increased the rate of glucose consumption and lactate production, whereas overexpression of PHLPP had the opposite effect. Bioenergetic analysis using Seahorse …

Crispr-Cas9 Mediated Nox4 Knockout Inhibits Cell Proliferation And Invasion In Hela Cells, Naser Jafari, Hyunju Kim, Rackhyun Park, Liqing Li, Minsu Jang, Andrew J. Morris, Junsoo Park, Cai Huang

Markey Cancer Center Faculty Publications

Increased expression of NOX4 protein is associated with cancer progression and metastasis but the role of NOX4 in cell proliferation and invasion is not fully understood. We generated NOX4 knockout HeLa cell lines using the CRISPR-Cas9 gene editing system to explore the cellular functions of NOX4. After transfection of CRISPR-Cas9 construct, we performed T7 endonuclease 1 assays and DNA sequencing to generate and identify insertion and deletion of the NOX4 locus. We confirmed the knockout of NOX4 by Western blotting. NOX4 knockout cell lines showed reduced cell proliferation with an increase of sub-G1 cell population and the decrease of S/G2/M …

Chloroquine-Inducible Par-4 Secretion Is Essential For Tumor Cell Apoptosis And Inhibition Of Metastasis, Ravshan Burikhanov, Nikhil Hebbar, Sunil K. Noothi, Nidhi Shukla, James Sledziona, Nathália Araujo, Meghana Kudrimoti, Qing Jun Wang, David S. Watt, Danny R. Welch, Jodi Maranchie, Akihiro Harada, Vivek M. Rangnekar

Radiation Medicine Faculty Publications

The induction of tumor suppressor proteins capable of cancer cell apoptosis represents an attractive option for the re-purposing of existing drugs. We report that the anti-malarial drug, chloroquine (CQ), is a robust inducer of Par-4 secretion from normal cells in mice and cancer patients in a clinical trial. CQ-inducible Par-4 secretion triggers paracrine apoptosis of cancer cells and also inhibits metastatic tumor growth. CQ induces Par-4 secretion via the classical secretory pathway that requires the activation of p53. Mechanistically, p53 directly induces Rab8b, a GTPase essential for vesicle transport of Par-4 to the plasma membrane prior to secretion. Our findings …

Genetic Analysis Of Serf Gene Function In Drosophila Melanogaster And Its Contribution To A Fly Model Of Spinal Muscular Atrophy, Swagata Ghosh

Theses and Dissertations--Biology

The Serf gene is evolutionarily highly conserved but its biological function is not known in any organism. In human, SERF1/H4F5 was first identified as a modifier of the disease Spinal Muscular Atrophy (SMA). SMA is caused by mutations in the Survival Motor Neuron 1(SMN1) gene leading to diminished levels of the Smn protein. More than 90% of patients with the most severe form of SMA have deletions that remove SERF1 as well as mutaions within SMN1. Hence, loss of Serf activity is hypothesized to exacerbate SMA disease progression. The primary motivation of this thesis was to test …