Arsenic trioxide exhibits potent antitumor effects in vitro and in vivo, and is widely used in the treatment of acute promyelocytic leukemia (APL) in humans. In addition to APL, arsenic is of potential therapeutic value for the treatment of other hematologic malignancies, including chronic myelogenous leukemia (CML). There is evidence...
Regulation of cell cycle and cell death are critical for normal cellular proliferation, tissue homeostasis, animal development, and the pathogenesis of human diseases such as cancer. Irregularities in cell cycle and cell death may result in tumorigenesis. In this dissertation, I describe my studies of a novel gene C53, which...
CD4-positive T cells express ligands for E- and P-selectins, carbohydrate-binding adhesion molecules that are induced on inflamed endothelium. The interaction between selectins and the selectin ligands facilitates the migration of T cells to sites of inflammation. The fucosyltransferase FucT-VII is essential for selectin ligand formation but the signaling and transcriptional...
The Gram-negative bacterium <em> Vibrio cholerae </em> elicits disease through the export of enterotoxins. The <em> V. cholerae </em> RTX toxin was identified due its ability to cause cell rounding. Characterization of the RTX toxin demonstrated that this cell rounding was due to the depolymerization of the actin cytoskeleton through...
Reactivation of latent human cytomegalovirus is of significant concern in immunocompromised transplant patients. However, the mechanisms controlling reactivation of latent CMV have not been understood. It is likely that reactivation is initiated by induction of IE gene expression. In this thesis, I studied molecular mechanisms leading to transcriptional activation of...
There is increasing evidence that links chronic activation of glial cells and the subsequent self-propagating cycle of neuroinflammation to the neurodegenerative progression of Alzheimer's disease (AD). Nevertheless, attempts to identify currently approved drugs capable of safely attenuating the neuroinflammatory processes in AD have proven disappointing to date, and the development...
><p><em>Vibrio cholerae</em>, the causative agent of the severe diarrheal disease cholera, secretes several "accessory" toxins including RTX toxin, which causes cross-linking of the actin cytoskeleton. The rtx locus of <em>V. cholerae</em> is located adjacent to the integrated CTX? prophage. The RTX toxin itself is encoded by the <em>rtxA</em> gene found...
Arsenic trioxide (As<sub>2</sub>0<sub>3</sub>) is an arsenic-derivative that exhibits potent growth inhibitory effects against malignant cells. The remarkable antitumor effects of As<sub>2</sub>0<sub>3</sub> in vitro and in vivo have prompted the development of various clinical trials that established its activity in acute promyelocytic leukemia (APL). As<sub>2</sub>0<sub>3</sub> is part of the standard treatment...
Most women diagnosed with epithelial ovarian carcinoma (EOC) initially present with metastases, but little is known about the regulation of ovarian tumor cell dissemination by the tumor microenvironment. Because ovarian cancer cell dissemination is mostly limited to the peritoneal cavity and often results in the accumulation of malignant ascites, the...
The primary function of the human urinary bladder is to store urine, while maintaining a permeability barrier that protects underlying tissues from noxious urinary components. Inflammatory diseases of the bladder, including urinary tract infection (UTI) and interstitial cystitis (IC), afflict millions of patients in the US annually and cause significant...
It is critical to genomic integrity that DNA is replicated completely and faithfully during each cell cycle. The essential replication factor Cdt1 is a critical protein in preventing reinitiation of replication. Overexpression of Cdt1 causes re-replication in p53 null cells and transforms NIH3T3 cells, causing them to form tumors in...
Epstein-Barr virus (EBV) is a human gamma-herpesvirus that primarily infects B cells and epithelial cells. While the glycoproteins required for entry into these two cell types differ, the gH/gL glycoprotein complex is essential for entry into both epithelial and B cells. Analysis of gH protein sequences from three gamma-herpesviruses: EBV,...
The ubiquitin-proteasome system degrades regulatory proteins and thereby controls a broad range of cellular processes such as the cell cycle, DNA-repair, gene transcription and signal transduction. The proteasome typically degrades its substrates completely into small peptides. However, biological exceptions do occur. For example, the activity of a handful of transcriptional...
Initial studies described the ability of CD4+CD25+ T regulatory (Treg) cells in suppressing autoimmune diseases in animal models. An emerging interest has focused on the potential role of Treg cells in cancer development and progression as they have been shown to suppress anti-tumor immunity. In the present study, CD4+CD25- T...
Breast cancer cells acquire many genetic alterations in apoptotic signaling pathways rendering them resistant to apoptosis. Human Epidermal growth factor Receptor-2 (HER-2/ErbB2/neu) is amplified or overexpressed in approximately 30% of breast and ovarian tumors and correlates with poor prognosis. Although HER-2 is an orphan receptor, it forms potent signaling heterodimers...
The response to reduced levels of oxygen (hypoxia) is essential for embryonic development by promoting the proper formation of vascular networks. Conversely, hypoxia also promotes the development of pathophysiological processes such as pulmonary hypertension and cancer. The main mediator of responses to hypoxia within the cell is the transcription factor...
Multiple Myeloma (MM) is an incurable plasma cell malignancy occurring within the bone marrow. Glucocorticoids (GCs) are widely used in the treatment of MM patients due to potent induction of apoptosis. Though known to occur via the glucocorticoid receptor (GR), the molecular details of GC-induced apoptosis in MM cells remain...
Prostate cancer (PCa) is the most commonly diagnosed cancer (1:6), and the second most common cause of cancer-related deaths in American men (>27,000/year). Metastasis is largely responsible for these deaths. During metastasis, tumor cells travel from the prostate to a distant organ where they establish a secondary tumor. Cell motility...
Barbed end regulation is critical to the formation of the actin-based protrusive structures, lamellipodia and filopodia. In this body of work we have chosen to focus on two main activities, filament termination by the heterodimeric Capping protein (CP) and continued filament elongation by the Ena/VASP family of proteins. We demonstrate...
Early growth response genes (Egr1-4) are induced as immediate early genes by a variety of extracellular stimuli that influence cellular growth and differentiation. Egr transcriptional regulators modulate gene expression by binding to Egr response elements (ERE) in target genes. In this study, the low affinity p75 neurotrophin receptor (p75NTR) was...