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The Role Of Autophagy And Senescence In The Responses Of Non-Small Cell Lung Cancer Cells To Chemotherapy And Radiation, Nipa H. Patel
The Role Of Autophagy And Senescence In The Responses Of Non-Small Cell Lung Cancer Cells To Chemotherapy And Radiation, Nipa H. Patel
Theses and Dissertations
Cancer-associated deaths account for the second-highest mortality rates in the United States. Primary modalities of treatment often include surgery, radiation, and chemotherapy, and may also incorporate targeted therapy and immunotherapy. However, resistance to these treatments remains high, resulting in disease reoccurrence and poor survival rates. While apoptosis or cell death of tumor cells is the ideal outcome for anti-cancer therapy, this is often not the case, and in fact cancer cells may upregulate several pathways, such as autophagy and senescence, as a means to undergo alternative cell fate and evade apoptotic cell death. An essential tumor suppressor gene, TP53, …
Cell Cycle Regulation Of Retinal Progenitors; A Role For The Nance-Horan Syndrome Protein In Retinogenesis, Paul J. Vorster
Cell Cycle Regulation Of Retinal Progenitors; A Role For The Nance-Horan Syndrome Protein In Retinogenesis, Paul J. Vorster
Theses and Dissertations
The Nance-Horan syndrome gene (NHS) plays a role in lens, eye and brain development. To date, the function of NHS remains unclear. Recent evidence showed that p53 isoform, Δ113p53, inhibits abnormal cell growth during organogenesis. We show that NHS is expressed in the retinas of Danio rerio and Xenopus tropicalis during key stages of retinogenesis, and that knockdown of the gene resulted in a small eye phenotype in both species. Initially, knockdown of nhsb in zebrafish had no visible defects at 24hpf. But examination of the retina at 48hpf, we see a marked difference in size compared to control embryos. …
Investigation Of Gain-Of-Function Induced By Mutant P53, Catherine Vaughan
Investigation Of Gain-Of-Function Induced By Mutant P53, Catherine Vaughan
Theses and Dissertations
p53 is mutated in 50% of all human cancers, and up to 70% of lung cancer. Mutant p53 is usually expressed at elevated levels in cancer cells and has been correlated with a poor prognosis. Cancer cells that express mutant p53 show an increase in oncogenic phenotypes including an increase in growth rate, resistance to chemotherapeutic drugs, and an increase in motility and tumorigenicity to name a few. We have identified several genes involved in cell growth and survival that are upregulated by expression of common p53 mutants: NFκB2, Axl, and epidermal growth factor receptor (EGFR). The aim of this …
Rheb Dynamics On Lysosomal Membranes Determines Mtorc1 Activity After Loss Of P53 Or Activation Of Ampk, Catherine M. Bell
Rheb Dynamics On Lysosomal Membranes Determines Mtorc1 Activity After Loss Of P53 Or Activation Of Ampk, Catherine M. Bell
Theses and Dissertations
The tumor suppressor TP53 is the most frequently altered gene in human cancers. The growth-promoting complex, mTORC1 plays a part of the oncogenic profile caused by dysfunctional p53. mTORC1 sits downstream of AMPK and other crucial tumor suppressors/oncogenes, PTEN, LKB1, and Akt. The antifolate pemetrexed was found by this laboratory to activate AMPK via the inhibition of the enzyme AICART in de novo purine synthesis. This work presents a mechanism of mTORC1 activation with p53 loss, as well as of mTORC1 inhibition by pemetrexed-induced AMPK. We have found that mTORC1 activity was substantially upregulated by the loss …
Pemetrexed, A Modulator Of Amp-Activated Kinase Signaling And An Inhibitor Of Wild Type And Mutant P53, Stuti Agarwal
Pemetrexed, A Modulator Of Amp-Activated Kinase Signaling And An Inhibitor Of Wild Type And Mutant P53, Stuti Agarwal
Theses and Dissertations
New drug discoveries and new approaches towards diagnosis and treatment have improved cancer therapeutics remarkably. One of the most influential and effective discoveries in the field of cancer therapeutics was antimetabolites, such as the antifolates. The interest in antifolates increased as some of the antifolates showed responses in cancers, such as mesothelioma, leukemia, and breast cancers. When pemetrexed (PTX) was discovered, our laboratory had established that the primary mechanism of action of pemetrexed is to inhibit thymidylate 22 synthase (TS) (E. Taylor et al., 1992). Preclinical studies have shown that PTX has a broad range of antitumor activity in human …
Isolation And Characterization Of Multipotent Lung Stem Cells From P53 Mutant Mice Models, Venkat Sundar Gadepalli
Isolation And Characterization Of Multipotent Lung Stem Cells From P53 Mutant Mice Models, Venkat Sundar Gadepalli
Theses and Dissertations
Recent advances in understanding lung biology have shown evidence for the existence of resident lung stem cells. Independent studies in identifying and characterizing these somatic lung stem cells have shown the potential role of these cells in lung repair and regeneration. Understanding the functional characteristics of these tissue resident stem/progenitor cells has gained much importance with increasing evidence of cancer stem cells, cells in a tumor tissue with stem cell characteristics. Lung cancer is most commonly characterized by loss of p53 function which results in uncontrolled cell divisions. Incidence of p53 point mutations is highest in lung cancer, with a …
The Effects Of Tarsh Overexpression On Lung Carcinomas, Young Kim
The Effects Of Tarsh Overexpression On Lung Carcinomas, Young Kim
Theses and Dissertations
Lung cancer arises from epithelial cells that line the air passages of the lungs. It is the second most common malignancy in the United States; trends suggest that over 228,000 new patients will be diagnosed with lung cancer in 2013. Due to the fact that lung cancer is highly aggressive, it has proven difficult to control. The 5-year survival rate has been shown to be only 15.9%, despite the advances made in terms of diagnosis and treatment. Therefore, we are faced with the problem of finding more effective methods that allow for an earlier diagnosis and the improved treatment of …
Exploring The Functional Interaction Between Camk-Ii And P53, Raymond Lai
Exploring The Functional Interaction Between Camk-Ii And P53, Raymond Lai
Theses and Dissertations
Calcium (Ca2+)/calmodulin-dependent kinase 2 (CaMK-II) is a multifunctional member of a family of Ca2+/calmodulin-dependent serine/threonine protein kinases that respond to transient intracellular calcium signaling. CaMK-II has been reported to be involved with transcription regulation, cell motility, neuronal development, cell cycle regulation, and more recently early development of vertebrates (Easley et al., 2008; Rothschild et al., 2009; Francescatto et al., 2010). Through previous work in the lab using tandem mass spectrometry and “substrate-trapping mutants”, tumor suppressor protein 53 (p53) was identified as a novel CaMK-II binding partner in tissue culture. In this study, I sought to provide characterization of the functional …
Identification Of Camk-Ii Protein Targets In Tissue Culture And Zebrafish Embryos Using Tandem Mass Spectrometry, Alexandra Myers
Identification Of Camk-Ii Protein Targets In Tissue Culture And Zebrafish Embryos Using Tandem Mass Spectrometry, Alexandra Myers
Theses and Dissertations
Calcium (Ca2+)/calmodulin-dependent kinase 2 (CaMK-II) is one member of a family of Ca2+/calmodulin-dependent protein kinases that responds to intracellular Ca2+ signals (Hudmon, A. and H. Schulman (2002)). CaMK-II is a multifunctional regulator of transcription, cell cycle progression, cell motility and neuronal development. (Wang, C., et al. (2008), Easley, C. A. IV, et al. (2008), Osterhoff, M., et al. (2003), Faison, M. O., et al. (2002)). Recently, CaMK-II has been shown to be important in the early development of vertebrates. In developing zebrafish, disruption of CaMK-II expression has been shown to induce phenotypes similar to those documented in several human diseases. …