Life Sciences Commons^™

Killerflip: A Novel Lytic Peptide Specifically Inducing Cancer Cell Death, B Pennarun, G. Gaidos, O Bucur, A Tinari

Dartmouth Scholarship

One of the objectives in the development of effective cancer therapy is induction of tumor-selective cell death. Toward this end, we have identified a small peptide that, when introduced into cells via a TAT cell-delivery system, shows a remarkably potent cytoxicity in a variety of cancer cell lines and inhibits tumor growth in vivo, whereas sparing normal cells and tissues. This fusion peptide was named killer FLIP as its sequence was derived from the C-terminal domain of c-FLIP, an anti-apoptotic protein. Using structure activity analysis, we determined the minimal bioactive core of killerFLIP, namely killerFLIP-E. Structural analysis of cells using …

Med13p Prevents Stress-Independent Mitochondrial Hyperfragmentation And Aberrant Apoptosis Activation In Saccharomyces Cerevisiae By Controlling Cyclin C Nuclear Localization, Svetlana Khakhina

Graduate School of Biomedical Sciences Theses and Dissertations

During aging, and as a result of environmental changes, cells are exposed to elevated levels of reactive oxygen species (ROS). High ROS levels induce lipid oxidation, protein aggregation, mitochondrial hyperfragmentation, DNA damage and programmed cell death (PCD), also called apoptosis. PCD is a highly regulated process and its misregulation has been linked to neurodegenerative diseases and cancer development.

Our hypothesis is that cyclin C plays a role in the initiation of apoptosis. During normal conditions, cyclin C represses the transcription of stress response genes (SRG). In response to stress, cyclin C translocates to the cytoplasm where it facilitates mitochondrial hyperfragmentation …

Modulation Of Bax/Bak Dependent Apoptosis By Sirtuin 3 And Mitochondrial Permeability Transition By Sirtuin 4, Manish Verma

Graduate School of Biomedical Sciences Theses and Dissertations

Mitochondria are dynamic organelles that regulate a myriad of cellular functions, including energy production and metabolic regulation. Mitochondria are also a critical regulator of cell death signaling cascades modulating both apoptotic and necrotic cell death. However, what determines which cell death pathway is activated is still unclear. The mitochondrial/intrinsic pathway of apoptosis is dependent on the activation of pro-apoptotic proteins, Bax and Bak, which induce mitochondrial outer membrane permeabilization (MOMP). Once the integrity of outer mitochondrial membrane (OMM) is compromised, pro-apoptotic intermembrane space proteins like cytochrome c, Smac/Diablo, Omi/HtrA2 and AIF are released into the cytoplasm, which activates the post-mitochondrial …

A Novel Cardiac Function Of Sumo2/3 And Senp5 Dependent Pathway And Its Physiological Impact On Congestive Cardiomyopathy, Eun Young Kim

Dissertations & Theses (Open Access)

A Novel cardiac function of SUMO2/3 and SENP5 dependent pathway and its physiologic impact on congestive cardiomyopathy

Publication No.___________

Eun Young Kim, M.S.

Supervisory professor: Robert J. Schwartz, Ph.D.

SUMOylation regulates diverse cellular processes including transcription, cell cycle, protein stability, and apoptosis. Although SUMO1 has been extensively studied so far, relevance of SUMO2/3 is unclear, especially in heart. Here we show that failing heart induces SUMO2/3 conjugation. Increased SUMO2/3-dependent modification leads to congestive heart disease such as cardiac hypertrophy by promoting cardiac cell death. Calpain2 and Calpastatin as a novel SUMO2 targets have been known to be involved in mitochondrial-independent …

Expression Of The Chemokine Receptor, Cxcr4, And Its Ligand, Sdf-1, Are Increased In Purkinje Cells Of The Multiple System Atrophy Cerebellum, Megan Welter

Masters Theses

Multiple System Atrophy (MSA) is a sporadic, neurodegenerative disease that consists of three conditions: autonomic dysfunction, Parkinsonism and cerebellar ataxia. Our lab conducted an Affymetrix global gene expression analysis using pons tissue of MSA patients to determine genes that are differentially expressed when compared to non- MSA controls. This study identified upregulated genes, including the C-X-C chemokine receptor type 4, CXCR4, to which stromal cell-derived factor-I (SDF-1) is the natural ligand. The CXCR4/SDF-1 signaling pair has been sho.wn to play multiple roles in the brain, such as inducing neuronal apoptosis and promoting leukocyte recruitment during inflammation. The MSA cerebellum presents …

The Role Of Nucleolin In B-Cell Lymphomas And Fas-Mediated Apoptotic Signaling, Jillian F. Wise

Dissertations & Theses (Open Access)

The death receptor Fas has a key role in mediating homeostasis, elimination of defective cells and more recently implicated in cancer promotion. Many effective anti-cancer therapies depend on Fas-mediated apoptosis to eradicate tumor cells and ineffective Fas-apoptotic signaling is a basis for primary as well as acquired resistance to chemotherapy. We hypothesized that Fas is subjected to direct regulation by inhibitory proteins attained by cancer cells. To screen for potential binding modulators of Fas, we analyzed lymphoma cells for Fas binding proteins. This purification scheme identified high scoring peptides derived from nucleolin, a nuclear protein known to be overexpressed in …

Oxidative Stress Based Strategies For Enhancing The Efficacy Of Histone Deacetylase Inhibitors (Hdaci), Nilsa Rivera-Del Valle

Dissertations & Theses (Open Access)

Histone deacetylase inhibitors (HDACi) are anti-cancer drugs that primarily act upon acetylation of histones, however they also increase levels of intracellular reactive oxygen species (ROS). We hypothesized that agents that cause oxidative stress might enhance the efficacy of HDACi. To test this hypothesis, we treated acute lymphocytic leukemia cells (ALL) with HDACi and adaphostin (ROS generating agent). The combination of two different HDACi (vorinostat or entinostat) with adaphostin synergistically induced apoptosis in ALL. This synergistic effect was blocked when cells were pre-treated with the caspase-9 inhibitor, LEHD. In addition, we showed that loss of the mitochondrial membrane potential is the …

Bovine Herpes Virus 1 (Bhv-1) And Herpes Simplex Virus Type 1 (Hsv-1) Promote Survival Of Latently Infected Sensory Neurons, In Part By Inhibiting Apoptosis, Clinton Jones

School of Veterinary and Biomedical Sciences: Faculty Publications

α-Herpesvirinae subfamily members, including herpes simplex virus type 1 (HSV-1) and bovine herpes virus 1 (BHV-1), initiate infection in mucosal surfaces. BHV-1 and HSV-1 enter sensory neurons by cell-cell spread where a burst of viral gene expression occurs. When compared to non-neuronal cells, viral gene expression is quickly extinguished in sensory neurons resulting in neuronal survival and latency. The HSV-1 latency associated transcript (LAT), which is abundantly expressed in latently infected neurons, inhibits apoptosis, viral transcription, and productive infection, and directly or indirectly enhances reactivation from latency in small animal models. Three anti-apoptosis genes can be substituted for LAT, which …

Nanosecond Pulsed Electric Field (Nspef) Ablation As An Alternative Or Adjunct To Surgery For Treatment Of Cancer, Ru Chen, Xinhua Chen, Stephen J. Beebe

Bioelectrics Publications

Surgery as resection or transplantation remains a fundamental means for cancer treatment and often offers an opportunity for a cure. However, surgery is not always possible because of tumor proximity to blood vessels or ducts or when a patient is not healthy enough to undergo surgery. Application of nanosecond pulsed electric fields (nsPEFs) is a new approach to treat cancer using pulse power technology that was originally designed for military purposes. This novel approach deposits extremely short pulses of high power, low energy electric fields into malignant tissues using electrodes to encompass tumors. Pre-clinical studies show that treatments are effective …

Regulation Of The Tumor Suppresser P53 And Survivin By Ras And Ral Gtpases:Implications For Malignant Transformation, Awet G. Tecleab

USF Tampa Graduate Theses and Dissertations

Abstract

Although the critical role of the small GTPases Ras and Ral in oncogenesis has been well documented, much remains to be investigated about the molecular mechanism by which these GTPases regulate malignant transformation. The work under this thesis made two major contributions to this field. The first is the discovery that K-Ras, RalA and/or RalB are required for the maintenance of the high levels of the anti-apoptotic protein survivin in some human cancer cells, and the second is the demonstration that down regulation of K-Ras, RalA and/or RalB, but not Raf-1 or Akt1/2, stabilizes the tumor suppressor p53 and …