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Full-Text Articles in Biochemistry, Biophysics, and Structural Biology

Mechanism Of Cyclin D1-Dependent Genomic Instability And Neoplastic Transformation, Laura Pontano Vaites Aug 2011

Mechanism Of Cyclin D1-Dependent Genomic Instability And Neoplastic Transformation, Laura Pontano Vaites

Publicly Accessible Penn Dissertations

Regulation of cyclin D1-dependent kinase activity is essential for cell cycle progression and DNA replication fidelity. Critically, impaired cyclin D1 phosphorylation and ubiquitin-mediated proteolysis following the G1/S transition drives neoplastic growth, suggesting that posttranslational regulation is required for cell homeostasis. Elucidation of mechanisms facilitating S-phase cyclin D1 accumulation and novel functions of nuclear cyclin D1/CDK4 kinase is critical for understanding the role of cyclin D1 in tumorigenesis. The work presented herein demonstrates that accelerated, Fbx4-dependent cyclin D1 degradation following S-phase DNA damage is essential to maintain genome stability. Furthermore, Fbx4 functions as a bona fide tumor suppressor, as ...


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 ...