Biochemistry, Biophysics, and Structural Biology Commons^™

Syk Promotes Tgf-Beta-Induced P-Body Clearance In Breast Cancer Cells Through The Enhancement Of Autophagy, Shana D. Hardy

Open Access Dissertations

SYK is a protein tyrosine kinase that plays an essential role in the development and activation of immune cells. Its expression, however, is not limited to immune cells. SYK is expressed in a variety of epithelial cell types and epithelial-derived tumors. Reports regarding the role of SYK expression in these diverse cell types and tumors have been opposing. In breast cancer, SYK expression has been overwhelmingly associated with tumor suppression. The loss of Syk expression is observed in invasive breast carcinoma tissue and cell lines and the reintroduction of Syk into metastatic breast cancer cells suppresses tumor growth and metastasis. …

Autophagic Turnover Of Inactive 26s Proteasomes In Yeast Is Directed By The Ubiquitin Receptor Cue5 And The Hsp42 Chaperone, Richard S. Marshall, Fionn Mcloughlin, Richard D. Vierstra

Biology Faculty Publications & Presentations

Highlights

• The yeast 26S proteasome is degraded by Atg8-mediated autophagy
• Nitrogen starvation and inactivation stimulate proteaphagy via distinct pathways
• Proteasome inhibition is accompanied by extensive ubiquitylation of the complex
• Proteaphagy engages the Cue5 autophagy receptor and the Hsp42 chaperone

Summary

The autophagic clearance of 26S proteasomes (proteaphagy) is an important homeostatic mechanism within the ubiquitin system that modulates proteolytic capacity and eliminates damaged particles. Here, we define two proteaphagy routes in yeast that respond to either nitrogen starvation or particle inactivation. Whereas the core autophagic machineries required for Atg8 lipidation and vesiculation are essential for both routes, the upstream Atg1 …

Inhibiting The Interaction Between Grp94 And Myocilin To Treat Primary Open-Angle Glaucoma, Andrew Stothert

USF Tampa Graduate Theses and Dissertations

Glaucoma is a neurodegenerative protein misfolding disorder classified by increases in IOP, damage to retinal ganglion cells (RGCs), optic nerve (ON) head damage, and progressive irreversible blindness. Primary open-angle glaucoma (POAG) is the most common form of glaucoma, constituting over 90% of clinical cases. POAG is observed in patients where normal outflow channels, mainly the trabecular meshwork (TM), are exposed at the angle formed by the iris and cornea. However, due to TM cellular dysfunction, aqueous outflow resistance is increased preventing normal circulation of aqueous humor. Recent studies have shown that in 2-4% of POAG cases, increased intracellular levels of …

Targeting Tau Degradation By Small Molecule Inhibitors For Treatment Of Tauopathies, Mackenzie Martin

USF Tampa Graduate Theses and Dissertations

Tauopathies are neurodegenerative diseases that affect millions of people around the world. Tauopathies include more than 20 neurodegenerative diseases. Some of the most common tauopathies are Alzheimer’s disease (AD), frontotemporal dementia (FTD), chronic traumatic encephalopathy (CTE), Pick’s disease, corticobasal degeneration, progressive supranuclear palsy (PSP), agyrophillic grain disease, and amyotrophic lateral sclerosis (ALS). These diseases can cause significant memory loss, behavioral changes, motor deficits and speech impairments. Tauopathies stem from accumulation of the microtubule associated protein tau (MAPT). Tau stabilizes microtubules and helps with axonal transport. In a disease state tau becomes hyperphosphorylated and truncated leading to its aggregation. More recently …

Axonal Transport And Life Cycle Of Mitochondria In Parkinson's Disease Model, Hyun Sung

Open Access Dissertations

In neurons, normal distribution and selective removal of mitochondria are essential for preserving compartmentalized cellular function. Parkin, an E3 ubiquitin ligase associated with familial Parkinson’s disease, has been implicated in mitochondrial dynamics and removal. However, it is not clear how Parkin plays a role in mitochondrial turnover in vivo, and whether the mature neurons possess a compartmentalized Parkin-dependent mitochondrial life cycle. Using the live Drosophila nervous system, here, I investigate the involvement of Parkin in mitochondrial dynamics; organelle distribution, morphology and removal. Parkin deficient animals displayed less number of axonal mitochondria without disturbing organelle motility behaviors, morphology and metabolic state. …

Tumor Suppressor Spred2 Interaction With Lc3 Promotes Autophagosome Maturation And Induces Autophagy-Dependent Cell Death, Ke Jiang, Min Liu, Guibin Lin, Beibei Mao, Wei Cheng, Han Liu, Jozsef Gal, Haining Zhu, Zengqiang Yuan, Wuguo Deng, Quentin Liu, Peng Gong, Xiaolin Bi, Songshu Meng

Molecular and Cellular Biochemistry Faculty Publications

The tumor suppressor Spred2 (Sprouty-related EVH1 domain-2) induces cell death in a variety of cancers. However, the underlying mechanism remains to be elucidated. Here we show that Spred2 induces caspase-independent but autophagy-dependent cell death in human cervical carcinoma HeLa and lung cancer A549 cells. We demonstrate that ectopic Spred2 increased both the conversion of microtubule-associated protein 1 light chain 3 (LC3), GFP-LC3 puncta formation and p62/SQSTM1 degradation in A549 and HeLa cells. Conversely, knockdown of Spred2 in tumor cells inhibited upregulation of autophagosome maturation induced by the autophagy inducer Rapamycin, which could be reversed by the rescue Spred2. These data …

Decorin As A Multivalent Therapeutic Agent Against Cancer., Thomas Neill, Liliana Schaefer, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Decorin is a prototypical small leucine-rich proteoglycan that epitomizes the multifunctional nature of this critical gene family. Soluble decorin engages multiple receptor tyrosine kinases within the target-rich environment of the tumor stroma and tumor parenchyma. Upon receptor binding, decorin initiates signaling pathways within endothelial cells downstream of VEGFR2 that ultimately culminate in a Peg3/Beclin 1/LC3-dependent autophagic program. Concomitant with autophagic induction, decorin blunts capillary morphogenesis and endothelial cell migration, thereby significantly compromising tumor angiogenesis. In parallel within the tumor proper, decorin binds multiple RTKs with high affinity, including Met, for a multitude of oncosuppressive functions including growth inhibition, tumor cell …

Mir494 Reduces Renal Cancer Cell Survival Coinciding With Increased Lipid Droplets And Mitochondrial Changes, Punashi Dutta, Edward Haller, Arielle Sharp, Meera Nanjundan

Molecular Biosciences Faculty Publications

Background: miRNAs can regulate cellular survival in various cancer cell types. Recent evidence implicates the formation of lipid droplets as a hallmark event during apoptotic cell death response. It is presently unknown whether MIR494, located at 14q32 which is deleted in renal cancers, reduces cell survival in renal cancer cells and if this process is accompanied by changes in the number of lipid droplets.

Methods: 769-P renal carcinoma cells were utilized for this study. Control or MIR494 mimic was expressed in these cells following which cell viability (via crystal violet) and apoptotic cell numbers (via Annexin V/PI staining) were …

Understanding The Interaction Between Ulk1 And Atg9 And Autophagy, Ryan Hyatt, Joshua L. Andersen

Journal of Undergraduate Research

Autophagy is an adaptive catabolic process of self-digestion, a process by which the cell recycles aged organelles and other structures. Interestingly, changes in the regulation of autophagy have been linked to infections, cancers, neurodegeneration, aging, and heart disease (Arroyo, Daniela S. et al. 2014). Understanding the mechanisms which control autophagy will aid in better treatment of those diseases, specifically in the development of effective pharmaceuticals.

Effect Of Hydroxychloroquine And Characterization Of Autophagy In A Mouse Model Of Endometriosis, A. Ruiz, S. Rockfield, N. Taran, E. Haller, Robert Engelman, I Flores, P Panina-Bordignon, Meera Nanjundan

Molecular Biosciences Faculty Publications

In endometriosis, the increased survival potential of shed endometrial cells (which normally undergo anoikis) is suggested to promote lesion development. One mechanism that may alter anoikis is autophagy. Using an autophagic flux inhibitor hydroxychloroquine (HCQ), we identified that it reduces the in vitro survival capacity of human endometriotic and endometrial T-HESC cells. We also identified that HCQ could decrease lesion numbers and disrupt lesion histopathology, as well as increase the levels of peritoneal macrophages and the IP-10 (10 kDa interferon-γ-induced protein) chemokine in a mouse model of endometriosis. We noted that RNA levels of a subset of autophagic …