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Full-Text Articles in Molecular Biology

Nucleoside Modifications Suppress Rna Activation Of Cytoplasmic Rna Sensors, Bart R. Anderson Dec 2010

Nucleoside Modifications Suppress Rna Activation Of Cytoplasmic Rna Sensors, Bart R. Anderson

Publicly Accessible Penn Dissertations

Multiple innate defense pathways exist to recognize and defend against foreign nucleic acids. Unlike innate immune receptors that recognize structures specific for pathogens that are not shared by mammalian hosts — for example, toll-like receptor (TLR)4-lipopolysaccharide, TLR5-flagellin, NOD1 and 2-peptidoglycan — all nucleic acids are made from four components that are identical from bacteria to man. Nucleoside modifications are prevalent in nature but vary greatly in their distribution and frequency, and therefore could serve as patterns for recognition of pathogenic nucleic acids. The presence of modified nucleosides in RNA reduces the activation of RNA-sensing TLRs and retinoic acid inducible gene I ...


Characterization Of Thap10 And Thap11 As Transcriptional Repressors In Dna Damage And Colon Cancer Progression, James B. Parker Dec 2010

Characterization Of Thap10 And Thap11 As Transcriptional Repressors In Dna Damage And Colon Cancer Progression, James B. Parker

Publicly Accessible Penn Dissertations

The THAP (Thanatos associated protein) domain is an evolutionarily conserved zinc-finger motif highly similar to the sequence specific DNA binding domain of Drosophila P element transposase. Emerging data suggest THAP proteins may function in DNA and chromatin dependent processes, including transcription. However, the transcriptional regulatory function, mechanisms of action, and role of most THAP proteins in normal and aberrant cellular processes remain largely unknown.

In this thesis, we demonstrate that several human THAP proteins contain transcriptional repressor activity and specifically identify THAP10 and THAP11 as differentially expressed in human DNA damage and colon cancer progression, respectively. THAP10 and THAP11 repressed ...


Utilizing Genetically Engineered Mouse Models Of Pancreatic Cancer: Evaluating The Role Of Cathepsin B And The Efficacy Of Farnesyl Thiosalicylic Acid, Aarthi Gopinathan Dec 2010

Utilizing Genetically Engineered Mouse Models Of Pancreatic Cancer: Evaluating The Role Of Cathepsin B And The Efficacy Of Farnesyl Thiosalicylic Acid, Aarthi Gopinathan

Publicly Accessible Penn Dissertations

I have utilized genetically engineered mouse models of pancreatic cancer to identify a potential new therapeutic target, and to test the efficacy of a putative ras inhibitor. In the first part, I show that cathepsin B is upregulated during disease progression in the mouse pancreas, as is overall cathepsin activity. Loss of cathepsin B decreases preinvasive disease burden and imparts a significant survival benefit, with a consistent decrease in proliferation. In addition, lack of cathepsin B also decreases the burden of liver metastasis. Phospho-Erk localization appears to be affected by cathepsin B loss, which may account for the defect in ...


Genomic Methods For Studying The Post-Translational Regulation Of Transcription Factors, Logan J. Everett Aug 2010

Genomic Methods For Studying The Post-Translational Regulation Of Transcription Factors, Logan J. Everett

Publicly Accessible Penn Dissertations

The spatiotemporal coordination of gene expression is a fundamental process in cellular biology. Gene expression is regulated, in large part, by sequence-specific transcription factors that bind to DNA regions in the proximity of each target gene. Transcription factor activity and specificity are, in turn, regulated post-translationally by protein-modifying enzymes. High-throughput methods exist to probe specific steps of this process, such as protein-protein and protein-DNA interactions, but few computational tools exist to integrate this information in a principled, model-oriented manner. In this work, I develop several computational tools for studying the functional implications of transcription factor modification. I establish the first ...


Mechanisms Of The Downregulation Of Prolactin Receptor And Their Role In Cell Proliferation, Bentley J. Varghese May 2010

Mechanisms Of The Downregulation Of Prolactin Receptor And Their Role In Cell Proliferation, Bentley J. Varghese

Publicly Accessible Penn Dissertations

Cells react to diverse stimuli by expressing specific receptors that recognize these stimuli and initiate specific signaling pathways that enable a cell to change with the environment. Downregulation of these signaling receptors represents the most direct method for limiting the magnitude and duration of downstream signal transduction. For cell surface transmembrane receptors, ligand-stimulated endocytosis is a major mechanism by which the ability of a cell to react to a ligand is restricted. In order to investigate the downregulation of the prolactin receptor (PRLr), we investigated the mechanism and key determinants in the endocytosis and downregulation of PRLr. In Chapter 2 ...


Functions Of Dna Damage Response Factors In Lymphocyte Development And Transformation, Bu Yin May 2010

Functions Of Dna Damage Response Factors In Lymphocyte Development And Transformation, Bu Yin

Publicly Accessible Penn Dissertations

DNA double strand breaks (DSBs) can activate cell cycle checkpoints or apoptosis, and lead to genomic alterations that drive malignant transformation. The H2AX core histone variant is phosphorylated in chromatin around DSBs by kinases such as ATM and DNA-PKcs. However, how H2AX suppresses chromosome breaks and translocations in cells and prevents tumorigenesis in mice and humans is not well understood. V(D)J recombination is a genetically programmed DNA damage and repair process that assembles the variable region exons of antigen receptor genes in developing lymphocytes. Using an inducible V(D)J recombination system, I found that H2AX is phosphorylated ...