Open Access. Powered by Scholars. Published by Universities.®
- Keyword
-
- Autophagy (2)
- AMPK (1)
- Acute myeloid leukemia (1)
- Affinity Purification (1)
- BH3 profiling (1)
-
- BMI (1)
- Bcl-2 family proteins (1)
- CREB (1)
- Cancer (1)
- Checkpoint (1)
- DIRAS (1)
- DNA repair (1)
- DSB (1)
- Diabetes (1)
- Drug resistance (1)
- Erk (1)
- Fat (1)
- G1 arrest (1)
- GTPase (1)
- Gastric cancer (1)
- Glucose (1)
- Immunotherapy (1)
- Insulin (1)
- KRas (1)
- Lung Cancer (1)
- MDM2 (1)
- MET (1)
- Mass Spectrometry (1)
- Mcl-1 (1)
- Melanoma (1)
Articles 1 - 7 of 7
Full-Text Articles in Medicine and Health Sciences
Insights Into The Therapeutic Potential Of Salt Inducible Kinase 1: A Novel Mechanism Of Metabolic Control, Randi Fitzgibbon
Insights Into The Therapeutic Potential Of Salt Inducible Kinase 1: A Novel Mechanism Of Metabolic Control, Randi Fitzgibbon
Dissertations & Theses (Open Access)
Salt inducible kinase 1 (SIK1) has been considered a stress-inducible kinase since it was first cloned in 1999. Continued efforts since this time have been dedicated to characterizing the structure and function of SIK1. Such research has laid the ground work for our understanding of SIK1 action and regulation in tissue and stimuli dependent manners. The fundamental findings of this dissertation continue in this tradition and include investigations of SIK1 regulatory mechanisms in skeletal muscle cells, the cellular and physiological effects of SIK1 loss of function in vitro and in vivo, and intracellular metabolic and mitochondrial regulation by this …
Involvement Of The Receptor For Advanced Glycation End Products (Rage) In Progression Of Pancreatic Cancer, Nancy Azizian Ms
Involvement Of The Receptor For Advanced Glycation End Products (Rage) In Progression Of Pancreatic Cancer, Nancy Azizian Ms
Dissertations & Theses (Open Access)
Oncogenic KRAS is central to several cancer types including pancreatic ductal adenocarcinoma (PDAC), but has been determined to be “undruggable”. Recent studies have indicated that oncogenic KRAS is not constitutively active but relies on a feed-forward stimulatory mechanism involving inflammation. In the current study we investigated the mechanisms by which, the receptor for advanced glycation end products (RAGE) affects and maintains KRAS activity. We observed that RAGE levels were elevated and there was a shift in the levels of specific isoforms upon inflammation in pancreatic cells and PDAC. Furthermore, RAGE agonists were found to increase Ras activity and downstream signaling …
Mechanisms Underlying The Sensitivity And Resistance Of Gastric Cancer Cells To Met Inhibitors, Rebecca Schroeder
Mechanisms Underlying The Sensitivity And Resistance Of Gastric Cancer Cells To Met Inhibitors, Rebecca Schroeder
Dissertations & Theses (Open Access)
MET amplification has been clinically credentialed as a therapeutic target in gastric cancer, but the molecular mechanisms underlying sensitivity and resistance to MET inhibitors are still not well understood. Using whole-genome mRNA expression profiling, we identified autophagy as a top molecular pathway that was activated by the MET inhibitor crizotinib in drug-sensitive human gastric cancer cells, and functional studies confirmed that crizotinib increased autophagy levels in the drug sensitive cells in a concentration-dependent manner. We then used chemical and molecular approaches to inhibit autophagy in order to define its role in cell death. The clinically available inhibitor of autophagy, chloroquine, …
Clinical And Therapeutic Significance Of Obesity In Melanoma, Jennifer L. Mcquade
Clinical And Therapeutic Significance Of Obesity In Melanoma, Jennifer L. Mcquade
Dissertations & Theses (Open Access)
While the FDA approval of targeted and immune therapies in metastatic melanoma (MM) have dramatically improved outcomes in this disease, de novo and/or acquired resistance can limit the clinical benefit of these agents. The IGF-1/PI3K/AKT pathway has been implicated in resistance to both targeted and immune therapy. The IGF-1/PI3K/AKT pathway has also been shown to play a key role in the pathogenesis of obesity in other malignancies. To date, the impact of energy balance on clinical outcomes and therapeutic response in MM has not been studied. I hypothesized that energy balance would impact the molecular biology, behavior, and drug sensitivity …
The Role Of The Diras Family Members In Regulating Ras Function, Cancer Growth And Autophagy, Margie Nicole Sutton
The Role Of The Diras Family Members In Regulating Ras Function, Cancer Growth And Autophagy, Margie Nicole Sutton
Dissertations & Theses (Open Access)
DIRAS3 is a maternally imprinted tumor suppressor gene that is downregulated by multiple mechanisms across several tumor types. When re-expressed, DIRAS3 decreases proliferation, inhibits motility, and induces autophagy and tumor dormancy. DIRAS3 encodes a 26 kDa small GTPase with 60% homology to Ras and Rap, differing from oncogenic Ras family members by a 34-amino acid N-terminal extension that is required for its tumor suppressive function in ovarian cancer. By assessing the structure-function relationship, I found that DIRAS3 inhibits Ras-induced transformation and is a natural antagonist of Ras/MAPK signaling. DIRAS3 binds directly to Ras and disrupts cluster formation inhibiting the activation …
Proteomic Identification Of Histone Post-Translational Modifications Induced By Dna Double-Strand Breaks And Novel Proteins Involved In The Dna Damage Response, Pingping Wang
Dissertations & Theses (Open Access)
Inaccurate repair of DNA double-strand breaks (DSBs) can lead to DNA mutation and chromosome rearrangements, causing human diseases such as cancer. Although we know the basic mechanisms of DSB repair, the added complexities in the chromatin context are unclear. This is partially due to the lack of unbiased systems for identifying proteins and post-translational modifications (PTMs) involved in DSB repair. In this work, we established a novel method, termed DSB-ChAP-MS (Double Strand Break-Chromatin Affinity Purification with Mass Spectrometry), for the affinity purification of a sequence-specific single copy endogenous chromosomal locus containing a DSB, followed by the proteomic identification of enriched …
Targeting Apoptotic Pathways To Overcome Drug Resistance In Acute Myeloid Leukemia, Rongqing Pan
Targeting Apoptotic Pathways To Overcome Drug Resistance In Acute Myeloid Leukemia, Rongqing Pan
Dissertations & Theses (Open Access)
Evasion of apoptosis is integral to tumorigenesis and drug resistance. BCL-2 and p53 proteins represent two focal nodes in convergent apoptosis signaling. Upregulation of anti-apoptotic BCL-2 family members and inactivation of p53 functions are two canonical approaches exploited by cancer cells to escape apoptosis. In the current study, we find that BCL-2 protein is highly expressed in acute myeloid leukemia (AML) cells. BCL-2–specific inhibitor ABT-199 potently induces mitochondrial apoptosis in AML cells and effectively kills AML stem/progenitor cells. Our biomarker studies demonstrate that both BH3 profiling and the expression profiling of BCL-2 proteins may serve as predictive biomarkers for the …