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Articles 1 - 16 of 16
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The Regulation Of Alternative Splicing By Oncogenic Signaling Pathways., Jacqueline Shultz
The Regulation Of Alternative Splicing By Oncogenic Signaling Pathways., Jacqueline Shultz
Theses and Dissertations
In the presented study, we demonstrate that the alternative splicing of caspase 9 was dysregulated in a large percentage of NSCLC tumors and cell lines. These findings led to the hypothesis that survival pathways activated by oncogenic mutation regulated this mechanism. Indeed, the oncogenic PI3-Kinase/Akt pathway was demonstrated to regulate the alternative splicing of caspase 9. Further mechanistic studies demonstrate that multiple Akt isoforms can regulate the alternative splicing of caspase 9 in NSCLC. Akt was additionally shown to mediate the exclusion of the exon 3,4,5,6 cassette of caspase 9 via the phospho-state of the RNA trans-factor, SRp30a. Mutagenesis studies …
Lysophosphatidic Acid Is A Mediator Of Interleukin-6 Production In Ovarian Cancer Cells, David Dang
Lysophosphatidic Acid Is A Mediator Of Interleukin-6 Production In Ovarian Cancer Cells, David Dang
Theses and Dissertations
Lysophosphatidic acid (LPA) is a naturally occurring bioactive lysophospholipid that mediates a broad range of cellular processes such as cell proliferation, survival, migration and invasion. LPA also plays a potential role in human oncogenesis as suggested by elevated expression of its receptors and its producing enzymes in malignant tissues. In the current study, we demonstrated that LPA is a potent mediator of interleukin-6 (IL-6) production in ovarian cancer. IL-6 is a pleiotropic cytokine which is thought to be an important mediator of ovarian cancer development and progression. Here, we demonstrated that IL-6 levels are indeed increased in the plasma of …
The Regulation Of Platelet Activating Factor Acetylhydrolase By Oxidized Phospholipids, Rachael Griffiths
The Regulation Of Platelet Activating Factor Acetylhydrolase By Oxidized Phospholipids, Rachael Griffiths
Theses and Dissertations
Platelet-activating factor acetylhydrolase (PAFAH) is elevated in atherosclerosis and may play a role in pathogenesis of this disease. Molecular mechanisms regulating the expression of this lipoprotein-associated PLA2 are indistinct. Mildy oxidized low density lipoprotein (oxLDL) and monocytes (the primary source of PAFAH) are co-localized in early atheromas. Monocytes are activated by oxidized phospholipids (oxPL) in the oxLDL particle. We hypothesized that oxPL-activated monocytes are the source of increased levels of PAFAH in atherosclerosis. We found that PAFAH expression is significantly induced by OxPAPC and in particular long-chain fractions of oxPAPC in monocytes and cytokine-differentiated DC, but not cytokine-differentiated MO. Furthermore, …
Analysis Of Secreted Phosphoprotein-24 And Its Effects During Osteoblast Differentiation In A Mesenchymal Stem Cell Model, Vasquez Jochen Granja
Analysis Of Secreted Phosphoprotein-24 And Its Effects During Osteoblast Differentiation In A Mesenchymal Stem Cell Model, Vasquez Jochen Granja
Theses and Dissertations
Musculoskeletal diseases, in particular osteoporosis, are increasingly becoming more prevalent in the U.S. due to the ageing population (Figure1). It is estimated that one-sixth of 300 million people in U.S. suffer from bone disorders or loss. About 10 million of those people above age 50 suffer from osteoporosis. Patients that suffer from osteoporosis have high morbidity and mortality rates. For instance, patients have decreased bone mineral density (BMD), a measurement of bone density that reflects the strength of bone as represented by calcium content. A decrease in BMD typically leads to an increased risk of bone fractures. In particular, hip …
Synergistic Growth Inhibition And Enhancement Of Cell Death By Combination Of Melanoma Differentiation Associated Gene-7 (Mda-7/Il-24) And Cisplatin In Ovarian Cancer Cell Lines, Renyan Liu
Theses and Dissertations
Ovarian cancer is the most lethal gynecological malignancy among women. The current first-line treatments for ovarian cancer are cisplatin, carboplatin and paclitaxel. However, resistance to these platinum-based drugs occurs in the large majority of initially responsive tumors, resulting in fully chemoresistant, fatal disease. Therefore, the resistance to cisplatin therapy has been a critical hurdle in the management of recurrent ovarian cancer. The mechanisms responsible for cisplatin resistance are not completely understood. In the search for new therapies to overcome/bypass cisplatin resistance, melanoma differentiation gene-7 (MDA-7) IL-24, which is a new cytokine, has anti-cancer efficacy by suppressing cell growth and inducing …
Intracellular Targets Of Sphingosine-1-Phosphate, Graham Michael Strub
Intracellular Targets Of Sphingosine-1-Phosphate, Graham Michael Strub
Theses and Dissertations
The bioactive lipid mediator sphingosine-1-phosphate (S1P) has emerged as a key regulator of a variety of important physiological functions, including cell growth, cell survival, cell motility, angiogenesis, lymphocyte trafficking, and mast cell function. S1P is formed by two different sphingosine kinases (SphKs) and binds to a family of 5 differentially expressed G-protein coupled receptors (S1PRs). The majority of research to date has focused on the activation of these receptors, but there is compelling evidence to suggest that S1P exerts intracellular functions independent of S1PRs. However no bona fide intracellular targets of S1P have been identified. In my dissertation, I have …
Sphingosine Kinase 1 Inhibitor, A Novel Inducer Of Autophagy, Daniel Meza
Sphingosine Kinase 1 Inhibitor, A Novel Inducer Of Autophagy, Daniel Meza
Theses and Dissertations
Autophagy is the process of “cell self-eating” which has been implicated both in cell survival and cell death. Sphingosine kinase 1 (SphK1) regulates the intracellular balance between ceramide and sphingosine, bioactive lipids associated with cell death, and sphingosine-1-phosphate (S1P), whose actions are associated with survival and proliferation. Previous studies have implicated upregulation of SphK1 in the induction of autophagy. In this study, SK1-I, a SphK1 specific competitive inhibitor, induced autophagy in a concentration and time dependent manner in HCT116 colorectal carcinoma cells. This autophagic response was observed to be more intense in wild type p53 expressing HCT116 cells than in …
Expression Of Chemokines And Vegfs In Hnscc, Crystal Cunningham
Expression Of Chemokines And Vegfs In Hnscc, Crystal Cunningham
Theses and Dissertations
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. The 5-year survival rate when the cancer remains as a primary tumor is 81% but when it metastasizes to distant sites, defined as a metastatic cancer, it decreases dramatically to 26%. Approaches to prevent these cancers from undergoing these metastatic changes can greatly improve the survival and outcome of these cancer victims. This current study is examining the expression profiles of chemokines and VEGFs in HNSCC. By investigation the underlying pathways involved in the expressions of chemokines and VEGFS we hope to sort out the transcriptional …
The Small Molecule Bcl-2 Inhibitor Ha14-1 Potentiates The Lethality Of A Regimen Combining Mek1/2 And Chk1 Inhibitors In Multiple Myeloma Cells, Leena Youssefian
The Small Molecule Bcl-2 Inhibitor Ha14-1 Potentiates The Lethality Of A Regimen Combining Mek1/2 And Chk1 Inhibitors In Multiple Myeloma Cells, Leena Youssefian
Theses and Dissertations
Previously, we have found that the co-administration of MEK1/2 inhibitors and Chk1 inhibitors synergistically induce multiple myeloma cell apoptosis through upregulation of the BH3-only pro-apoptotic protein Bim. However, these apoptotic events were largely blocked by the characteristic over-expression of Bcl-2 of Bcl-xL in multiple myeloma cells. HA14-1, a small molecule Bcl-2 inhibitor, may therefore circumvent this resistance to apoptosis by blocking Bcl-2 and Bcl-xL anti-apoptotic protein actions. In our project, we hypothesize that the co-administration of HA14-1 with MEK/Chk1 inhibitors will enhance apoptosis in multiple myeloma (MM) cells. To test this hypothesis, we exposed MM cells U266 and RPMI8226, or …
Role Of The Porphyromonas Gingivalis Ecf Sigma Factor, Sigh, In Oxidative Stress Response, Sara Sarrafee
Role Of The Porphyromonas Gingivalis Ecf Sigma Factor, Sigh, In Oxidative Stress Response, Sara Sarrafee
Theses and Dissertations
Periodontal disease affects a majority of the US population. Porphyromonas gingivalis is the major etiological agent for development and progression of the disease. P. gingivalis is a hemin-dependent, obligate anaerobe that is found predominantly in periodontal pockets in infected patients. So for, little is known regarding the mechanisms which allow P. gingivalis to survive and sustain itself in the oral cavity. To better understand the adaptive mechanisms of the bacterium to the varying conditions in the oral cavity, regulatory mechanisms must be characterized. Sigma factors (σ) are responsible for initiating transcription by guiding RNA polymerase binding to specific DNA promoter …
The Second Generation Proteasome Inhibitor Carfilzomib Interacts Synergistically With Hdac Inhibitors In Diffuse Large B-Cell Lymphoma Cells Through Multiple Mechanisms And Circumvents Bortezomib Resistance, Dmitry Lembersky
Theses and Dissertations
Mechanisms underlying the interactions between the proteasome inhibitor carfilzomib and HDAC inhibitors were examined in both germinal center (GC) and activated B-cell (ABC) subtypes of human diffuse large B-cell lymphoma (DLBCL). Simultaneous exposure to minimally toxic concentrations of carfilzomib and HDAC inhibitor vorinostat resulted in the release of mitochondrial pro-apoptotic proteins SMAC and cytochrome c, pro-apoptotic caspase activation, and synergistic induction in apoptosis in both ABC and GC DLBCL subtypes. These events were associated with a marked increase in the stress kinase JNK, ROS generation, G2-M cell cycle arrest, as well as induction of DNA damage. Genetic knockdown of JNK …
The Role Of Brca1 In Dna Double-Strand Break Repair, Seth Dever
The Role Of Brca1 In Dna Double-Strand Break Repair, Seth Dever
Theses and Dissertations
Mutations in the breast cancer susceptibility 1 (BRCA1) gene are linked to breast as well as ovarian cancers. However, most cancer-causing mutations within the BRCA1 gene have been found in the N’ and C’ terminal regions of the BRCA1 protein, both believed to be important for DNA double-strand break (DSB) repair. The BRCA1 C’ terminal (BRCT) repeats have been implicated in phospho-serine protein binding whereas the N’ terminal RING domain interacts with the BARD1 protein to form a hetero-dimeric complex with E3 ubiquitin ligase activity. The BRCA1 BRCT domain binds CtIP, BACH1, and RAP80, all of which have been directly …
Scribble As A Possible Binding Partner For The Map Kinases Erk2 And Erk6, William Allen
Scribble As A Possible Binding Partner For The Map Kinases Erk2 And Erk6, William Allen
Theses and Dissertations
We worked on finding a new kinase regulator to develop basic data to be used for cancer prevention. Our work found a link between three previously unrelated proteins involved in cancer, ERK2 and ERK6 and Scribble. The MAP kinase cascade is involved in cell proliferation, which is highly deregulated in cancer. Through the screening of ERK6 associating molecules, we found the cell polarity, and cell cycle related molecule Scribble. Furthermore, we found that Scribble was a dual-specific kinase regulator. We clearly demonstrated that these ERKs interact with Scribble through the LRR and the PDZ domains of Scribble. We hypothesize that …
Novel Mechanisms Regulating Cytokine-Induced Gene Expression In Astrocytes And Glioblastoma Cells, Lauren Bryan
Novel Mechanisms Regulating Cytokine-Induced Gene Expression In Astrocytes And Glioblastoma Cells, Lauren Bryan
Theses and Dissertations
Chronic inflammation in the brain results in the development of several CNS diseases, including Alzheimer’s and Parkinson’s diseases, multiple sclerosis, and tumors. IL-1, a pro-inflammatory cytokine released by activated microglia and astrocytes, instigates the expression of factors promoting the progression of these CNS disorders, including cytokines, chemokines, and components of matrix remodeling systems, such as the plasminogen activator system. IL-1 also increases the mRNA expression and activity of SphK, the enzyme that phosphorylates Sph to form S1P, a bio-active sphingolipid. This thesis demonstrates that IL-1 and S1P enhance the mRNA and protein expression of PAI-1 and uPAR, two key components …
Molecular Mechanisms For Regulation Of Gene Expression By Lysophosphatidic Acid In Ovarian Carcinoma Cells, Regina Oyesanya
Molecular Mechanisms For Regulation Of Gene Expression By Lysophosphatidic Acid In Ovarian Carcinoma Cells, Regina Oyesanya
Theses and Dissertations
Lysophosphatidic acid (LPA) is a potent bioactive phospholipid mediator that functions through multiple G protein couple receptors (GPCRs). LPA is elevated in ascites of ovarian cancer patients and is involved in growth, survival and metastasis of ovarian cancer cells. Gene promoter analyses revealed that some LPA-target genes share similar sets of binding sites for prominent transcription factors posing the possibility of a general mechanism for activation of their expression by LPA. Detailed investigation of the mechanisms of regulation of cyclooxygenase 2 (Cox-2), a paradigm of LPA-regulated genes, showed that LPA robustly upregulated the expression of Cox-2 in ovarian cancer cells …
Role Of Rock And Pkc In Regulation Of Contraction Of Permeabilized Femoral Arterial Smooth Muscle, Brendan Browne
Role Of Rock And Pkc In Regulation Of Contraction Of Permeabilized Femoral Arterial Smooth Muscle, Brendan Browne
Theses and Dissertations
KCl is traditionally used as a stimulus to examine the role of increases in cytosolic Ca2+ on the regulation of smooth muscle contraction. KCl bypasses GPCR activation, thereby avoiding activation of additional cell signaling systems, such as phospholipase C and PKC that are inherent to Gaq and Ga12/13 stimulation. GPCR activation causes Ca2+ sensitization (greater force for a given increase in Ca2+) by a ROCK- and PKC-dependent inhibition of myosin light chain (MLC) phosphatase. Recent studies have demonstrated that KCl can also produce Ca2+ sensitization, implying that Ca2+ itself may induce Ca2+ sensitization. To test the hypothesis that Ca2+ can …