Cell and Developmental Biology Commons^™

Pentachlorophenol Decreases Tumor-Cell-Binding Capacity And Cell-Surface Protein Expression Of Human Natural Killer Cells, Tasia Hurd, Jasmine Walker, Margaret M. Whalen

Chemistry Faculty Research

Pentachlorophenol (PCP) is an organochlorine pesticide that decreases the tumor-cell killing (lytic) function of human natural killer (NK) cells. NK cells defend against tumor cells and virally infected cells. They bind to these targets, utilizing a variety of cell-surface proteins. This study examined concentrations of PCP that decrease lytic function for alteration of NK binding to tumor targets. Levels of PCP that caused loss of binding function were then examined for effects on expression of cell-surface proteins needed for binding. Exposure to 10 µm PCP for 24 h (which caused a greater than 70% loss of lytic function) decreased NK …

A Shared Gene Expression Signature In Mouse Models Of Ebv-Associated And Non-Ebv-Associated Burkitt Lymphoma, Kathryn T. Bieging, Kamonwan Fish, Subbarao Bondada, Richard Longnecker

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The link between EBV infection and Burkitt lymphoma (BL) is strong, but the mechanism underlying that link has been elusive. We have developed a mouse model for EBV-associated BL in which LMP2A, an EBV latency protein, and MYC are expressed in B cells. Our model has demonstrated the ability of LMP2A to accelerate tumor onset, increase spleen size, and bypass p53 inactivation. Here we describe the results of total gene expression analysis of tumor and pretumor B cells from our transgenic mouse model. Although we see many phenotypic differences and changes in gene expression in pretumor B cells, the transcriptional …

Suppression Of Chronically Induced Breast Carcinogenesis And Role Of Mesenchymal Stem-Like Cells, Kusum Rathore

Doctoral Dissertations

Sporadic breast cancers are mainly attributable to long-term exposure to environmental factors, via a multi-year, multi-step, and multi-path process of tumorigenesis involving cumulative genetic and epigenetic alterations in the chronic carcinogenesis of breast cells from a non-cancerous stage to precancerous and cancerous stages. Epidemiologic and experimental studies have suggested that various dietary compounds like green tea and grape seed may be used as preventive agents for breast cancer control. In this research, I have developed a cellular model that mimics breast cell carcinogenesis chronically induced by cumulative exposures to low doses of environmental carcinogens. I used the chronic carcinogenesis model …

The Utilization Of Mouse Models To Study Gene Functions: The Role Of Foxn3 And Chd2 In Murine Development And Cancer, George Azaz Samaan

Doctoral Dissertations

Murine model organisms are an essential tool in the scientific community quest to decipher the molecular etiology of human diseases. Currently, several methods are used to induce or reproduce human diseases in mouse models using advanced genetic engineering techniques to mutate the wild-type genes. We utilized the Baygenomics gene-trap method to study the effects of two mammalian genes: FOXN3 and CHD2. The Forkhead Box (FOX) family of transcription factors shares a common DNA-binding domain and has been associated with organ development, differentiation, cell growth and proliferation, and cancer. Meanwhile, the CHD (Chromodomain helicase DNA binding protein) family of proteins is …

The Role Of E2f1 In The Response To Dna Double Strand Breaks, Jie Chen

Dissertations & Theses (Open Access)

The importance of E2F transcription factors in the processes of proliferation and apoptosis are well established. E2F1, but not other E2F family members, is also phosphorylated and stabilized in response to various forms of DNA damage to regulate the expression of cell cycle and pro-apoptotic genes. E2F1 also relocalizes and forms foci at sites of DNA double-strand breaks but the function of E2F1 at sites of damage is still unknown. Here I reveal that E2F1 deficiency leads to increased spontaneous DNA break and impaired recovery following exposure to ionizing radiation. In response to DNA double-strand breaks, NBS1 phosphorylation and foci …

Regulation Of Hgf Expression By Δegfr-Mediated C-Met Activation In Glioblastoma Cells, Jeannine Garnett

Dissertations & Theses (Open Access)

Overexpression of the hepatocyte growth factor receptor (c-Met) and its ligand, the hepatocyte growth factor (HGF), and a constitutively active mutant of the epidermal growth factor receptor (∆EGFR/EGFRvIII), occur frequently in glioblastoma. c-Met is activated in a ligand-dependent manner by HGF or in a ligand-independent manner by ∆EGFR. Dysregulated c-Met signaling contributes to the aggressive phenotype of glioblastoma, yet the mechanisms underlying the production of HGF in glioblastoma are poorly understood. We found a positive correlation between HGF and c-Met expression in glioblastoma, suggesting that they are coregulated. This is supported by the finding that in a c-Met/HGF axis-dependent glioblastoma …

Identification Of Factors Involved In Dna Methylation Of Cpg-Island-Promoters, Yan Zhang

Dissertations & Theses (Open Access)

Repression of many tumor suppressor genes (TSGs) in cancer is mediated by aberrantly increased DNA methylation levels at promoter CpG islands (CGI). About one-fourth of empirically defined human promoters are surrounded by or contain clustered repetitive elements. It was previously observed that a sharp transition of methylation occurs between highly methylated repetitive elements (SINE or LINE) and unmethylated CGI-promoters (e.g. P16, VHL, CDH and RIL) in normal tissues. The functions that lead to increased CGI methylation in cancer remain poorly understood. We propose that CGI-promoters contain cis-elements for triggering de novo DNA methylation. In the first part of our project, …

Function Of Znf668 In Cancer Development, Ruozhen Hu

Dissertations & Theses (Open Access)

Human cancer develops as a result of accumulation of mutations in oncogenes and tumor suppressor genes. Zinc finger protein 668 (ZNF668) has recently been identified and validated as one of the highly mutated genes in breast cancer, but its function is entirely unknown. Here, we report two major functions of ZNF668 in cancer development.

(1) ZNF668 functions as a tumor suppressor by regulating p53 protein stability and function. We demonstrate that ZNF668 is a nucleolar protein that physically interacts with both MDM2 and p53. By binding to MDM2, ZNF668 regulates MDM2 autoubiquitination and prevents MDM2-mediated p53 ubiquitination and degradation; ZNF668 …

The Role Of Receptor Tyrosine Kinase Axl In Pancreatic Ductal Adenocarcinoma And Its Regulation By Hematopoietic Progenitor Kinase 1, Xianzhou Song

Dissertations & Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive malignancies with less than 5% of five year survival rate. New molecular markers and new therapeutic targets are urgently needed for patients with PDA. Oncogenic receptor tyrosine kinase Axl has been reported to be overexpressed in many types of human malignancies, including diffuse glioma, melanoma, osteosarcoma, and carcinomas of lung, colon, prostate, breast, ovary, esophagus, stomach, and kidney. However, the expression and functions of Axl in PDA are unclear. We hypothesized that Axl contributes to the development and progression of PDA. We examined Axl expression in 54 human PDA samples …

The Role Of Tak1 In Pancreatic Cancer Development, Qianghua Xia

Dissertations & Theses (Open Access)

Pancreatic cancer is the fourth leading cause of cancer-related mortality in the United States and the fifth leading cause of cancer-related mortality worldwide. Pancreatic cancer is a big challenge in large due to the lack of early symptoms. In addition, drug resistance is a major obstacle to the success of chemotherapy in pancreatic cancer. The underlying mechanism of drug resistance in human pancreatic cancers is not well understood. Better understanding of the mechanism of molecular pathways in human pancreatic cancers can help to identify the novel therapeutic target candidates, and develop the new preventive and clinic strategies to improve patient …

Mcnamara 2011 Mpmicro - Multi-Probe Microscopy (10/31/2011), George Mcnamara

George McNamara

Multi-Probe Microscopy is an ~1500 page Word document summarizing what I know and/or found interesting in light microscopy, fluorescence microscopy and digital image analysis, from 1995-2005. Very little has been updated since 2005.

Role Of Hypoxia And Glycolysis In The Development Of Multi-Drug Resistance In Human Tumor Cells And The Establishment Of An Orthotopic Multi-Drug Resistant Tumor Model In Nude Mice Using Hypoxic Pre-Conditioning, Lara Milane, Zhenfeng Duan, Mansoor M. Amiji

Mansoor M. Amiji

Background The development of multi-drug resistant (MDR) cancer is a significant challenge in the clinical treatment of recurrent disease. Hypoxia is an environmental selection pressure that contributes to the development of MDR. Many cancer cells, including MDR cells, resort to glycolysis for energy acquisition. This study aimed to explore the relationship between hypoxia, glycolysis, and MDR in a panel of human breast and ovarian cancer cells. A second aim of this study was to develop an orthotopic animal model of MDR breast cancer. Methods Nucleic and basal protein was extracted from a panel of human breast and ovarian cancer cells; …

Ziram Activates Mitogen-Activated Protein Kinases And Decreases Cytolytic Protein Levels In Human Natural Killer Cells, Thyneice R. Taylor, Margaret M. Whalen

Chemistry Faculty Research

Human natural killer (NK) cells are central in immune defense with their ability to lyse tumor cells and virally infected cells. Tumor formation and viral infection may increase if NK cytotoxic function is disrupted. Ziram (zinc dithiocarbamate) is used as an accelerating agent in the production of latex and to protect various fruits and vegetables from fungal infection. Previously, we have shown that exposure to ziram inhibits NK lytic function. Butyltin environmental contaminants, which also inhibit NK lytic function, cause rapid activations of mitogen-activated protein kinases (MAPKs) and decreases in expression of the cytolytic proteins granzyme B and perforin (after …

Defining The Role Of Nras In Melanoma Maintenance, Sravya T. Challa, Sheri L. Holmen

Undergraduate Research Opportunities Program (UROP)

The incidence of melanoma has increased 600 percent over the last four decades; it is the most rapidly increasing malignancy among young people in the United States and is currently the leading cause of cancer death in women aged 25- 29. If detected early, the disease is easily treated; however, once the disease has metastasized it is largely refractory to conventional therapies and is associated with a high mortality rate. The development of cancer from a pre-malignant primary tumor to a metastatic cancer that develops at secondary sites is a multi-step process, thought to require many genetic and epigenetic events …

Study Of Rest As A Negative Regulator Of P16ink4a, Monica B. Gireud

Dissertations & Theses (Open Access)

STUDY OF REST AS A NEGATIVE REGULATOR OF P16^INK4A

Monica Gireud, B.S.

Thesis Advisor: Vidya Gopalakrishnan, Ph.D.

The RE1 Silencing Transcription Factor (REST) is a negative regulator of neuronal differentiation. It is expressed ubiquitously in early embryos, but downregulated in neural progenitors concomitant with onset of neuronal differentiation in these cells. REST has been widely studied as a negative regulator of neuronal differentiation genes. Our recent work identified a novel role for REST in control of cell proliferation. However, the underlying molecular mechanism(s) are not known and is a focus of the current thesis project. Here, we provide evidence …

Role Of Prostaglandin E2 In The Regulation Of Pancreatic Stellate Cells Hyper Activity Associated With Pancreatic Cancer, Chantale Charo

Dissertations & Theses (Open Access)

Pancreatic cancer is one of the most lethal type of cancer due to its high metastasis rate and resistance to chemotherapy. Pancreatic fibrosis is a constant pathological feature of chronic pancreatitis and the hyperactive stroma associated with pancreatic cancer. Strong evidence supports an important role of cyclooxygenase-2 (COX-2) and COX-2 generated prostaglandin E2 (PGE2) during pancreatic fibrosis. Pancreatic stellate cells (PSC) are the predominant source of extracellular matrix production (ECM), thus being the key players in both diseases. Given this background, the primary objective is to delineate the role of PGE2 on human pancreatic stellate cells (PSC) hyper activation associated …

Downregulation Of Pax2 Suppresses Ovarian Cancer Cell Growth, Huijuan Song

Dissertations & Theses (Open Access)

PAX2 is one of nine PAX genes regulating tissue development and cellular differentiation in embryos. PAX2 promotes cell proliferation, oncogenic transformation, cell-lineage specification, migration, and survival. Unattenuated PAX2 has been found in several cancer types. We therefore sought to elucidate the role of PAX2 in ovarian carcinomas. We found that PAX2 was expressed in low-grade serous, clear cell, endometrioid and mucinous cell ovarian carcinomas, which are relatively chemoresistant compared to high grade serous ovarian carcinomas. Four ovarian cancer cell lines, RMUGL (mucinous), TOV21G (clear cell), MDAH-2774 (endometrioid) and IGROV1 (endometrioid), which express high-levels of PAX2, were used to study the …

Developmental Deregulation And Tumorigenesis Inhibition In 14-3-3zeta Knockout Mouse, Jun Yang

Dissertations & Theses (Open Access)

Cancer is second leading cause of death in the United States. Improving cancer care through patient care, research, education and prevention not only saves lives, but reduces health care cost as well. Breast cancer is the most leading cause of cancer incidence and cancer related death in women of the United States. 14-3-3s are a family of conserved proteins ubiquitously expressed in all eukaryotic organisms. They form complexes with hundreds of proteins by binding to specific phospho-serine/threonine containing motifs. In this way they regulate a variety of cellular processes and are involved in many human diseases especially cancer to our …

Enforced Expression Of Tbx1 In Fetal Thymic Epithelial Cells Antagonizes Thymus Organogenesis, Kim T. Cardenas

Dissertations & Theses (Open Access)

Enforced expression of Tbx1 in fetal thymic epithelial cells antagonizes

thymus organogenesis

Kim T. Cardenas

The thymus and parathyroid glands originate from organ-specific domains of 3rd pharyngeal pouch (PP) endoderm. At embryonic day 11.5 (E11.5), the ventral thymus and dorsal parathyroid domains can be identified by Foxn1 and Gcm2 expression respectively. Neural crest cells, (NCCs) play a role in regulating patterning of 3rd PP endoderm. In addition, pharyngeal endoderm influences fate determination via secretion of Sonic hedgehog (Shh), a morphogen required for Gcm2 expression and generation of the parathyroid domain. Gcm2 is a downstream target of the transcription factor Tbx1, …

Crosstalk Between R1175 Methylation And Y1173 Phosphorylation Negatively Modulates Egfr-Mediated Erk Activation, Jung-Mao Hsu

Dissertations & Theses (Open Access)

Post-translational protein modifications are critical regulators of protein functions as they expand the signaling potentials of the modified proteins, leading to diverse physiological consequences. Currently, increasing evidence suggests that protein methylation is as important as other post-translational modifications in the regulation of various biological processes. This drives us to ask whether methylation is involved in the EGFR (epidermal growth factor receptor) signaling, a biological process extensively regulated by multiple post-translational modifications including phosphorylation, glycosylation and ubiquitination. We found that EGFR R1175 is methylated by a protein arginine methyltransferase named PRMT5. During EGFR activation, PRMT5-mediated R1175 methylation specifically enhances EGF-induced EGFR …

Mechanisms Of Adenovirus-Mediated Autophagy, Erin White

Dissertations & Theses (Open Access)

A patient diagnosed with a glioma, generally, has an average of 14 months year to live after implementation of conventional therapies such as surgery, chemotherapy, and radiation. Glioblastomas are highly lethal because of their aggressive nature and resistance to conventional therapies and apoptosis. Thus other avenues of cell death urgently need to be explored. Autophagy, which is also known as programmed cell death type II, has recently been identified as an alternative mechanism to kill apoptosis- resistant cancer cells. Traditionally, researchers have studied how cells undergo autophagy during viral infection as an immune response mechanism, but recently researchers have discovered …

The Role Of Cancer-Associated Fibroblasts In Lung Tumorigenesis, Jonathon D. Roybal

Dissertations & Theses (Open Access)

The extracellular milieu is rich in growth factors that drive tumor progression,but the mechanisms that govern tumor cell sensitivity to those ligands have notbeen fully defined. In this study, we address this question in mice that developmetastatic lung adenocarcinomas through the suppression of the microRNA-200 (miR-200) family. Cancer-associated fibroblasts (CAF) enhance tumorgrowth and invasion by secreting VEGF-A that binds to VEGFR1, a processrequired for tumor growth and metastasis in mice and correlated with a poorprognosis in lung adenocarcinoma patients. In this study, we discovered thatmiR-200 blocked CAF-induced tumor cell invasion by directly targetingVEGFR1 in tumor cells. In the context of …

Mechanisms Of Adenovirus-Mediated Autophagy, Erin White

Dissertations & Theses (Open Access)

A patient diagnosed with a glioma, generally, has an average of 14 months year to live after implementation of conventional therapies such as surgery, chemotherapy, and radiation. Glioblastomas are highly lethal because of their aggressive nature and resistance to conventional therapies and apoptosis. Thus other avenues of cell death urgently need to be explored. Autophagy, which is also known as programmed cell death type II, has recently been identified as an alternative mechanism to kill apoptosis- resistant cancer cells. Traditionally, researchers have studied how cells undergo autophagy during viral infection as an immune response mechanism, but recently researchers have discovered …

Na/K-Atpase Mimetic Pnaktide Peptide Inhibits The Growth Of Human Cancer Cells, Zhichuan Li, Zhongbing Zhang, Joe X. Xie, Xin Li, Jiang Tian, Ting Cai, Hongaun Cui, Hanfei Ding, Joseph I. Shapiro Md, Zijian Xie

Biochemistry and Microbiology

Cells contain a large pool of non-pumping Na/K-ATPase that participates in signal transduction. Here, we show that the expression of α1 Na/K-ATPase is significantly reduced in human prostate carcinoma as well as in several human cancer cell lines. This down-regulation impairs the ability of Na/K-ATPase to regulate Src-related signaling processes. Supplement of pNaKtide, a peptide derived from α1 Na/K-ATPase, reduces activities of Src and Src effectors. Consequently, these treatments stimulate apoptosis and inhibit growth in cultures of human cancer cells. Moreover, administration of pNaKtide inhibits angiogenesis and growth of tumor xenograft. Thus, the new findings demonstrate the in vivo effectiveness …

Metastatic Disease: Interactions Between Tumor Cells And Host Environment During Cancer Cell Spread, Jennifer M. Maclean

Electronic Thesis and Dissertation Repository

Tumor and metastasis formation are not cell autonomous phenomena, but rather an evolution of disease within and responding to the host environment. Metastatic spread from a primary tumor occurs as a result of a complex interplay between tumor cells and the host, wherein tumor cells must escape the primary tumor, enter the host vasculature, travel to and arrest in a distant tissue and survive and grow in that new organ. It is known that cells that progress through these stages must both escape and exploit host systems, yet the mechanisms used are not fully understood. Therefore, the goal of this …

Nod2, Rip2 And Irf5 Play A Critical Role In The Type I Interferon Response To Mycobacterium Tuberculosis, Amit K. Pandey, Yibin Yang, Zhaozhao Jiang, Sarah M. Fortune, Francois Coulombe, Marcel A. Behr, Katherine A. Fitzgerald, Christopher M. Sassetti, Michelle A. Kelliher

Katherine A. Fitzgerald

While the recognition of microbial infection often occurs at the cell surface via Toll-like receptors, the cytosol of the cell is also under surveillance for microbial products that breach the cell membrane. An important outcome of cytosolic recognition is the induction of IFNalpha and IFNbeta, which are critical mediators of immunity against both bacteria and viruses. Like many intracellular pathogens, a significant fraction of the transcriptional response to Mycobacterium tuberculosis infection depends on these type I interferons, but the recognition pathways responsible remain elusive. In this work, we demonstrate that intraphagosomal M. tuberculosis stimulates the cytosolic Nod2 pathway that responds …

Tetrabromobisphenol A Decreases Cell-Surface Proteins Involved In Human Natural Killer (Nk) Cell–Dependent Target Cell Lysis, Tasia Hurd, Margaret M. Whalen

Chemistry Faculty Research

Human natural killer (NK) lymphocytes are able to destroy tumor cells and virally-infected cells. Interference with their function can leave an individual with increased susceptibility to cancer development and/or viral infection. We have shown that the tumor-destroying (lytic) function of NK cells can be dramatically decreased by exposure to the environmental contaminant tetrabromobisphenol A (TBBPA). TBBPA is a flame retardant used in a variety of materials including circuit boards, carpeting, and upholstery and has been found in human blood samples. TBBPA interferes with NK cell lytic function, in part, by decreasing the ability of NK cells to bind to target …

Variations In Mre11/Rad50/Nbs1 Status And Dna Damage-Induced S-Phase Arrest In The Cell Lines Of The Nci60 Panel, Kristen M. K. Garner, Alan Eastman

Dartmouth Scholarship

The Mre11/Rad50/Nbs1 (MRN) complex is a regulator of cell cycle checkpoints and DNA repair. Defects in MRN can lead to defective S-phase arrest when cells are damaged. Such defects may elicit sensitivity to selected drugs providing a chemical synthetic lethal interaction that could be used to target therapy to tumors with these defects. The goal of this study was to identify these defects in the NCI60 panel of cell lines and identify compounds that might elicit selective cytotoxicity.

Mechanistic Study Of The Small Molecule Inhibitor Dx-52-1, Junru Cui

Master's Theses

Cell migration is a basic biological process that is fundamental to several normal and disease processes such as embryonic development, tissue repair, immune function, angiogenesis and cancer cell invasion and metastasis. Small organic molecules inhibiting cell migration can be used as both research probes and therapeutic agents. DX-52-1, a semisynthetic derivative of the natural product quinocarmycin (also known as quinocarcin), inhibits the migration of Madin-Darby canine kidney epithelial cells with nanomolar concentration. We have identified galectin-3, a multifunctional protein whose best-known function is its sugar binding ability, as a secondary target of DX-52-1 with functions in cell motility. In addition, …

Muc4 Modulation Of Ligand-Independent Erbb2 Signaling, Goldi Attias Kozloski

Goldi A Kozloski

The membrane mucin Muc4 is a heterodimer, bi-functional glycoprotein complex that is normally expressed in epithelial tissue. Functional studies on the extracellular mucin subunit of Muc4 have shown that it acts to promote anti-adhesion properties by sterically interfering with cell-cell and cell-matrix interactions and that the extent of this effect is directly associated with the number of tandem repeats on this subunit. Functional studies on the transmembrane subunit of Muc4 have shown that this subunit participates in intracellular signaling through interaction with the receptor tyrosine kinase ErbB2. This role of Muc4 was shown to be mediated by stabilizing the heregulin …