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The Mechanism Of Regulation Of Autosomal Heterochromatic Genes In Drosophila Melanogaster Males By Rox Rna And Msl Proteins, Satya Kiran Koya

Wayne State University Dissertations

In humans and flies, males and females have different set of sex chromosomes contributing to different levels of X-linked gene expression. To equalize X-linked gene dosage between sexes, both humans and flies developed independent strategies which are called dosage compensation. Human females randomly inactivate one of their X chromosome into barr body and Drosophila males up regulate their single X chromosome two fold. Both strategies equalize of X linked gene dose between sexes.

In Drosophila, dosage compensation is brought about by the ribonucleoprotein Male Specific Lethal (MSL) complex that binds hundreds of sites along the X chromosome and modifies …

Matriptase Mediated C-Met Signaling In Breast Cancer, Gina Lynn Zoratti

Wayne State University Dissertations

MATRIPTASE MEDIATED c-MET SIGNALING IN CRITICAL FOR BREAST CANCER PROGRESSION

by

GINA ZORATTI

Historically proteases have been associated with tumor progression and metastasis through degradation of the basement membrane. However, in recent years these enzymes have also been shown to play key roles in the activation of growth factors and cytokines, thereby activating pro-oncogenic signaling pathways. Matriptase (MT-SP1, ST14) is an epithelia-specific pericellular protease which has received considerable attention in recent years spurred by the consistent dysregulation of the protease in human epithelial tumors including breast cancer. We have performed both functional and mechanistic studies of matriptase in breast cancer …

General Transcription Factors Play Dual Roles In Initiation And Termination, Scott Alan Medler

Wayne State University Dissertations

Gene looping, defined as the interaction of the promoter and the terminator regions of a gene during transcription, is emerging as an important gene regulatory mechanism in eukaryotes. The role of promoter bound general transcription factors during initiation is well established. However, recent studies have revealed that some initiation factors also interact with the 3' end of a gene. The biological role of initiation factors at the 3' end of a gene is unknown. The general transcription factors TFIIB and TFIIH have been found to interact genetically with Ssu72, a component of CPF 3' end processing complex. Accordingly, we found …

Cytogenetic Evaluation Of Low Dose Hyper-Radiosensitivity In Human Lymphoblastoid Cell Lines Exposed To Cobalt-60 Gamma Radiation., Gnanada Sameer Joshi

Wayne State University Dissertations

The dose-effect relationships of cells exposed to ionizing radiation are frequently described by linear quadratic (LQ) models over an extended dose range. However, many mammalian cell lines, when acutely irradiated in G2 at doses below 30 cGy, show hyper-radiosensitivity (HRS) as measured by reduced clonogenic cell survival, thereby indicating greater cell lethality than is predicted by extrapolation from high-dose responses. We therefore hypothesized that the cytogenetic response in G2 cells to low doses would also be steeper than predicted by LQ extrapolation from high doses. We tested our hypothesis by exposing four normal human lymphoblastoid cell lines to 0 - …

Bystander Effects Due To Neutrons, And Low-Dose Hyper-Radiosensitivity To Gamma Rays In Human Cells Using Cytogenetics, Isheeta Seth

Wayne State University Dissertations

Chapter 2:

Micronuclei have been used extensively in studies as an easily-evaluated indicator of DNA damage but little is known about their association with other types of damage such as nucleoplasmic bridges and nuclear buds. Radiation-induced clastogenic events were evaluated via the cytokinesis-block micronucleus assay in two normal human lymphoblastoid cell lines exposed to neutrons or gamma radiation. Micronuclei, nucleoplasmic bridges and nuclear buds were enumerated by recording the coincident presence of these endpoints within individual cells, and the associations among these three endpoints were evaluated for all treatment conditions. The common odds ratios for micronuclei and nucleoplasmic bridges were …

Characterization And Identification Of Novel Regulators Of The Synthesis Of Phospholipids, Cunqi Ye

Wayne State University Dissertations

Phospholipids are the most abundant lipids in cell membranes. The synthesis of phospholipids is crucial for cellular membrane biogenesis and nearly all aspects of cellular processes. Understanding the regulation of synthesis of phospholipids is beneficial to our fundamental knowledge of cell biology as well as human health.

Regulation of the synthesis of phospholipids is intensively studied in the yeast S. cerevisiae. Most notably, the synthesis of phospholipids is coordinated with the synthesis of inositol, a precursor of inositol-containing lipids, by controlling expression of the genes encoding phospholipid biosynthetic enzymes. In addition to this well-characterized regulatory circuit controlled by the …

Role Of The Pkna And Pknb Kinases In Mycobacterium Tuberculosis, Tripti Anandan

Wayne State University Dissertations

To respond to environmental changes, M. tuberculosis possesses eleven "eukaryotic-type" Ser/Thr protein kinases. The aim of the study described in this dissertation was to identify role of two of these kinases; PknA and PknB that are essential in M. tuberculosis. Two approaches are described to screen for potential in vivo substrates of PknA/PknB. First approach is based on proteomic search by over-expressing PknA/PknB in M. tuberculosis. Proteomic search led to identification of proteasome to be a substrate of PknA and PknB in M. tuberculosis. Furthermore, I demonstrate that the phosphorylation of PrcA and PrcB by PknA regulates processing of Pre-PrcB. …

Regulation Of Inositol Biosynthesis And Cellular Consequences Of Inositol Depletion: Implications For The Mechanism Of Action Of Valproate, Rania M. Deranieh

Wayne State University Dissertations

Inositol is a six-carbon cyclitol that is ubiquitous in biological systems. It is a precursor for the synthesis of numerous biologically important compounds, including inositol phosphates and phosphoinositides that are essential for cell function and viability. Inositol compounds play a role in membrane formation, gene regulation, signaling, regulation of ion channels, and membrane trafficking. Furthermore, inositol regulates hundreds of genes, including those involved in the biosynthesis of inositol and phospholipids. While transcriptional regulation of inositol biosynthesis has been extensively studied and well characterized, regulation of inositol biosynthesis at the enzymatic level has not been addressed. The current study shows that …

Sex And Heterochromatin: An Investigation Of Sexual Dimorphism In Drosophila Melanogaster, Manasi S. Apte

Wayne State University Dissertations

Over 30% of Drosophila genome is assembled into heterochromatin. Heterochromatin is relatively gene poor, transcriptionally less active and remains condensed during interphase. Previous studies established that roX RNA and some of the Male Specific Lethal (MSL) proteins, all components of the dosage compensation complex, are required for full expression of autosomal heterochromatic genes in male flies but not in females. This was surprising since heterochromatin is generally not thought to be sexually dimorphic. The genetic basis for the regulation of sex-specific heterochromatin was completely unknown.

To determine if roX RNAs localize directly at the heterochromatic regions that they regulate, I …

The Tumor-Suppressive Role Of Secreted Maspin Via The Exosomes, Ivory Dean

Wayne State University Dissertations

This dissertation highlights several novel findings. Maspin has been consistently detected in the conditioned media of maspin-expressing cells of normal and tumor breast, prostate and lung origin. Furthermore, extracellular maspin has been demonstrated to have anti-tumor effects. Interestingly, maspin has been reported as cargo of the exosomes, which highlights one of the secretion mechanisms of maspin. Maspin secretion as an exosomal molecule was verified by electron microscopy, atomic force microscopy, light scattering dynamic analysis and immunoblot analysis.

The data showed that exosomes derived from the non-malignant cell lines have two distinct populations that do no overlap in their size distributions. …