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Full-Text Articles in Cell Biology

Regulation Of Canonical And Non-Canonical Hippo Pathway Components In Mitosis And Cancer, Seth Stauffer Dec 2018

Regulation Of Canonical And Non-Canonical Hippo Pathway Components In Mitosis And Cancer, Seth Stauffer

Theses & Dissertations

The Hippo pathway is conserved regulator of organ size through control of proliferation, apoptosis, and stem-cell self-renewal. In addition to this important function, many of the canonical signaling members have also been shown to be regulated during mitosis. Importantly, Hippo pathway components are frequently dysregulated in cancers and have attracted attention as possible targets for improved cancer therapeutics. Further exploration of Hippo-YAP (yes-associated protein) signaling has revealed new regulators and effectors outside the canonical signaling network and has revealed a larger non-canonical network of signaling proteins in which canonical Hippo pathway components crosstalk with important cellular homeostasis and apoptosis signaling ...


The Role Of Yes-Associated Protein 1 In Ovarian Physiology And Pathology, Xiangmin Lv Dec 2017

The Role Of Yes-Associated Protein 1 In Ovarian Physiology And Pathology, Xiangmin Lv

Theses & Dissertations

Ovarian granulosa cells are the major somatic components of the ovarian follicle. Proper proliferation and differentiation of ovarian granulosa cells are essential for successful follicle development. Accumulating evidence indicates that the Hippo-YAP signaling pathway plays critical roles in both development and tumorigenesis of several organs. The present study aims to investigate the role of Yes-associated protein 1 (YAP) in ovarian granulosa cell proliferation, differentiation, and malignant transformation. At first, we found that nuclear YAP (active) was highly expressed in proliferative granulosa cells, whereas cytoplasmic YAP (inactive) was detected mainly in terminally-differentiated luteal cells. Further studies suggested that endogenous YAP activity ...


Identifying The Role Of Janus Kinase 1 In Mammary Gland Development And Breast Cancer, Barbara Swenson Dec 2017

Identifying The Role Of Janus Kinase 1 In Mammary Gland Development And Breast Cancer, Barbara Swenson

Theses & Dissertations

The development of the postnatal mammary gland is tightly controlled by peptide hormones and cytokines. The signaling of these extracellular ligands through their corresponding receptors rely on Janus Kinases (JAKs) that activate downstream Signal Transducers and Activators of Transcription (STATs). The JAK/STAT signaling pathway is crucial for processes such as growth, proliferation, and cell survival of the epithelial tissue, but also for the breakdown and remodeling of the mammary gland via IL-6 class inflammatory cytokines (e.g. LIF and OSM). JAK1 and JAK2, which are expressed in the mammary gland, are thought to have redundant functions. However, our previous ...


Role Of Ezrin In Colorectal Cancer Cell Survival Regulation, Premila Leiphrakpam Dec 2017

Role Of Ezrin In Colorectal Cancer Cell Survival Regulation, Premila Leiphrakpam

Theses & Dissertations

Colorectal cancer (CRC) is the second most common cause of cancer related deaths in the United States, mainly due to metastasis to the distant organ sites. However, the molecular basis of CRC metastasis is poorly understood. Therefore, identification and characterization of novel potential anti-cancer therapeutic targets CRC is of urgent need. Utilizing a 2D-DIGE proteomics approach ezrin was identified as a protein that is differentially expressed between primary colon tumors xenografts, orthotopically implanted in athymic nude mice, and corresponding and liver metastatic deposits. Ezrin, a cytoskeletal protein belonging to the ezrin–radixin–moesin (ERM) family plays important roles in cell ...


Molecular Mechanisms Of C-Terminal Eps15 Homology Domain Containing (Ehd) Protein Function, Kriti Bahl Jul 2017

Molecular Mechanisms Of C-Terminal Eps15 Homology Domain Containing (Ehd) Protein Function, Kriti Bahl

Theses & Dissertations

Endocytic trafficking is not only an essential process for the maintenance of cellular homeostasis but also plays a vital role in regulating diverse cellular processes such as signaling, migration and cell division. The C-terminal Eps 15 Homology Domain proteins (EHD1-4) play pivotal roles in regulating distinct steps of endocytic trafficking. Among the EHDs, EHD2 is disparate both in terms of sequence homology (70%) and its subcellular localization at the caveolae. The crystal structure of EHD2 has been solved and it contains an unstructured loop consisting of two proline-phenylalanine (PF) motifs: KPFRKLNPF. However, the other paralogs EHD1, EHD3 ...


The Role Of Ehd2 In Triple-Negative Breast Cancer Tumorigenesis And Progression, Timothy A. Bielecki May 2017

The Role Of Ehd2 In Triple-Negative Breast Cancer Tumorigenesis And Progression, Timothy A. Bielecki

Theses & Dissertations

Triple-negative breast cancer (TNBC) comprises 10%-15% of all breast cancer cases, yet is clinically challenging due to lack of targeted therapies which leads to higher mortality. Molecular subtyping has identified the most aggressive subclasses of breast cancer to be enriched in components of caveolae. While caveolae have been linked to many biological processes, their precise role in TNBC is still poorly understood. EHD2, a member of the C-terminal EPS15-Homology Domain-containing (EHD) protein family, has emerged as a new regulator of caveolae dynamics and is essential to maintain a stable membrane pool of caveolae. Studies in model cells demonstrate that ...


Regulation Of Alteration/Deficiency In Activation 3 (Ada3) By Acetylation And Its Role In Cell Cycle Regulation And Oncogenesis, Shashank Srivastava Dec 2016

Regulation Of Alteration/Deficiency In Activation 3 (Ada3) By Acetylation And Its Role In Cell Cycle Regulation And Oncogenesis, Shashank Srivastava

Theses & Dissertations

The ADA3 (Alteration/Deficiency in Activation 3) protein is a transcriptional adaptor protein that was initially discovered as a component of several HAT (Histone Acetyltransferase) complexes, the enzyme complex responsible for histone acetylation, which is a prerequisite for transcription. Earlier the studies from Dr. Band’s laboratory and that of others’ have deciphered a crucial role of ADA3 in cell cycle regulation (both through G1/S and G2/M phase transitions) and in maintaining the genomic stability.

While our laboratory investigated the mechanism behind the role of ADA3 in G1/S transition, the same remained unknown for ...


Defining The Role Of Phosphorylation And Dephosphorylation In The Regulation Of Gap Junction Proteins, Hanjun Li Dec 2016

Defining The Role Of Phosphorylation And Dephosphorylation In The Regulation Of Gap Junction Proteins, Hanjun Li

Theses & Dissertations

Gap junctions are intercellular channels that permit the free passage of ions, small metabolites, and signaling molecules between neighboring cells. In the diseased human heart, altered ventricular gap junction organization and connexin expression (i.e., remodeling) are key contributors to rhythm disturbances and contractile dysfunction. Connexin43 (Cx43) is the dominant gap junction protein isoform in the ventricle which is under tight regulation by serine/tyrosine phosphorylation. Phosphorylation and dephosphorylation regulate many aspects of Cx43 function including trafficking, assembly and disassembly, electrical and metabolic coupling at the plaque, as well as to modulate the interaction with other proteins.

Serine phosphorylation has ...


Mitogen And Morphogen Signaling Dysregulation: Pathophysiological Influence In Pancreatic Cancer And Alzheimer’S Disease, Eric Cruz Dec 2016

Mitogen And Morphogen Signaling Dysregulation: Pathophysiological Influence In Pancreatic Cancer And Alzheimer’S Disease, Eric Cruz

Theses & Dissertations

Although the etiology of a particular disease will vary, there are genetic and epigenetic bottlenecks that frequently converge resulting in dysregulation of mitogenic and morphogenetic signaling. This propensity is acutely experienced in malignancy and neurodegenerative disease.

Here, we have first investigated the role of dysregulated signaling in the context of pancreatic cancer (PC). Morphogenetic signaling has been regarded as a pleiotropic pathway with the potential to promote and inhibit metastatic features. Our investigation of bone morphogenetic protein 2 (BMP-2), an archetypical member of the BMP superfamily, has revealed the presence of extracellular, intracellular, and long non-coding RNA products. Our findings ...


Role Of Ddr1 In Pancreatic Cancer, Huocong Huang Aug 2016

Role Of Ddr1 In Pancreatic Cancer, Huocong Huang

Theses & Dissertations

Pancreatic ductal adenocarcinomas are highly malignant cancers, characterized by extensive invasion into surrounding tissues, metastasis to distant organs at a very early stage, and a limited response to therapy. One of the main features of pancreatic ductal adenocarcinomas is desmoplasia, which leads to extensive deposition of collagen I. We have demonstrated that collagen I can induce epithelial-mesenchymal transition (EMT) in pancreatic cancer cells. A hallmark of EMT is an increase in the expression of a mesenchymal cadherin, N-cadherin. Our previous studies have shown that up-regulation of N-cadherin can promote tumor cell invasion and that collagen I-induced EMT is through two ...


The Mechanism Of Tubular Recycling Endosome Biogenesis, Shuwei Xie Aug 2016

The Mechanism Of Tubular Recycling Endosome Biogenesis, Shuwei Xie

Theses & Dissertations

Endocytic trafficking is a critical process for cellular homeostasis, and multiple ailments that include cardiovascular disease and cancer are related to the dysregulation of endocytic transport. As vesicles and target membranes are key to endocytic transport, lipids are essential for the regulation of endocytic trafficking pathways. We have shown that the tubular recycling endosomes (TRE) are essential for the regulation of endocytic recycling pathways. However, the mechanisms by which TRE are biosynthesized and carry out their functions remain unsolved. Studies from our lab have shown that phosphatidic acid (PA) recruits Molecule Interacting with Casl-Like protein 1 (MICAL-L1) as well as ...


Inflammation- And Cancer-Associated Neurolymphatic Remodeling And Cachexia In Pancreatic Ductal Adenocarcinoma, Darci M. Fink May 2016

Inflammation- And Cancer-Associated Neurolymphatic Remodeling And Cachexia In Pancreatic Ductal Adenocarcinoma, Darci M. Fink

Theses & Dissertations

This work addresses two understudied elements of inflammation and malignancy—namely, (1) neurolymphatic remodeling during transitions in microenvironmental inflammatory status and (2) the systemic paraneoplastic inflammatory syndrome cancer-associated cachexia in the context of pancreatic adenocarcinoma (PDAC). Lymphatic vessels undergo dramatic phenotypic changes in initial inflammation, wound recovery, and recurrent inflammation. We identified complementary novel neuroremodeling behaviors under these conditions and hypothesized that both nerve and lymphatic remodeling were directed by a tissue remodeling factor with overlapping functions. We found that nerve growth factor (NGF) influenced not only nerves but also lymphatics. NGF stimulated lymphangiogenesis, inhibited lymphatic vessel regression during wound ...


Sprouty 2: A Novel Attenuator Of B Cell Receptor And Mapk Signaling In Chronic Lymphocytic Leukemia, Ashima Shukla May 2016

Sprouty 2: A Novel Attenuator Of B Cell Receptor And Mapk Signaling In Chronic Lymphocytic Leukemia, Ashima Shukla

Theses & Dissertations

Clinical heterogeneity is a major barrier to effective treatment of Chronic Lymphocytic Leukemia (CLL). Emerging evidence suggests that constitutive activation of various signaling pathways plays a role in the heterogeneous clinical outcome of CLL patients. MAPK-Erk signaling represents one such pathway with a demonstrated role in CLL pathogenesis. In this study, we have investigated the role of Sprouty2 (SPRY2) as a negative regulator of receptor and non-receptor tyrosine kinase signaling in the pathogenesis of CLL. We show that SPRY2 expression is significantly decreased in CLL cells, particularly from poor prognosis patients compared to those from good prognosis patients. Over-expression of ...


Defining The Role Of Interferon Regulatory Factor 4 In Chronic Lymphocytic Leukemia., Vipul Shukla May 2016

Defining The Role Of Interferon Regulatory Factor 4 In Chronic Lymphocytic Leukemia., Vipul Shukla

Theses & Dissertations

Chronic Lymphocytic Leukemia (CLL) represents the most common adult leukemia in the Western hemisphere. Despite considerable progress in our current understanding of CLL, this disease remains incurable and the molecular events underlying the complex pathogenesis of CLL are not fully elucidated. Interferon Regulatory Factor 4 (IRF4) belongs to the IRF superfamily of transcription factors that has been shown to play critical roles at multiple stages of B cell development. Interestingly, a Genome Wide Association Study identified Single Nucleotide Polymorphism (SNP) mediated IRF4 down regulation, as a major predisposing genetic event during the development of CLL. However, whether low levels of ...


Role Of Cell Type And Genetic Alterations In Driving Breast Cancer Pathogenesis, Divya Bhagirath May 2016

Role Of Cell Type And Genetic Alterations In Driving Breast Cancer Pathogenesis, Divya Bhagirath

Theses & Dissertations

Breast cancer is the second most leading cause of death among women in the United States. Several environmental and genetic factors contribute to the pathogenesis of the disease. It is classified into different subtypes based on expression of certain markers as well as that of set of genes that define the disease progression and associated mortality. Identification of various subtypes namely: Luminal-like (Luminal-A, Luminal-B), ErbB2 over-expressing, Basal-like and Claudin low types, showed an association of survival outcomes with that of the corresponding gene expression signatures, thus paving a way for therapeutic intervention. It further emphasizes the importance of nature of ...


A Role For Ehd Family Endocytic Regulators In Endothelial Biology, Alexandra E. J. Moffitt Dec 2015

A Role For Ehd Family Endocytic Regulators In Endothelial Biology, Alexandra E. J. Moffitt

Theses & Dissertations

Endocytic trafficking is an essential process in eukaryotic cells, specifically for the transport of nutrients, membrane components, and receptors. Cargo destined for endocytic traffic is internalized at the cell surface via clathrin-dependent and clathrin-independent pathways, and brought to the early or sorting endosomes. From there, cargo is further trafficked to lysosomes for degradation, trafficked to other compartments in the cell, or recycled back to the cell surface (either directly or via the endocytic recycling compartment).

Mammalian C-terminal Eps15 homology domain-containing proteins, or EHD proteins (EHD1 to 4), are a family of highly conserved ATPases that function as key regulators of ...


The Role Of Tumor Suppressor Co-Chaperone Chip/Stub1 In Erbb2-Mediated Oncogenesis, Haitao Luan Dec 2015

The Role Of Tumor Suppressor Co-Chaperone Chip/Stub1 In Erbb2-Mediated Oncogenesis, Haitao Luan

Theses & Dissertations

The epidermal growth factor receptor (EGFR) family member ErbB2 (Her2) is overexpressed in 20 -30% of invasive breast cancers and this overexpression correlates with poor prognosis and shorter overall as well as disease-free survival. Aberrant expression of ErbB2 through gene amplification, transcriptional deregulation and/or altered endocytic trafficking results in overexpression of ErbB2 at the plasma membrane and biases ErbB2 from primarily ligand-driven hetero-dimerization under normal expression conditions to increased ligand-independent homo-dimer and hetero-dimer formation and consequent activation. C-terminus of HSC70-Inteeracting protein (CHIP)/STIP1-homologous U-Box containing protein 1 (STUB1) is an HSP90/HSC70 interacting negative co-chaperone known to promote ubiquitination ...


Acute Methamphetamine Exposure Affects Histone Modifying Enzymes And Cytokine Production In Macrophages, Ariel Burns Dec 2015

Acute Methamphetamine Exposure Affects Histone Modifying Enzymes And Cytokine Production In Macrophages, Ariel Burns

Theses & Dissertations

The effects of methamphetamine (Meth) in the periphery are not well studied and a comprehensive investigation on the effects and molecular mechanism will give insight into why Meth users are at an increased risk of infections. For this reason, we use macrophages as a model for the immune system dysregulation seen in Meth abusers and also because macrophages are a long-lived cell that HIV infects and persists in. We aimed to determine the effects of Meth on the cytokine production, histone modifying enzymes and the corresponding histone post-translational modifications, and the molecular mechanism in HIV-infected human macrophages treated with combination ...


Role Of Hippo-Yap Signaling In Mitosis And Prostate Cancer, Lin Zhang Aug 2015

Role Of Hippo-Yap Signaling In Mitosis And Prostate Cancer, Lin Zhang

Theses & Dissertations

The Hippo pathway controls organ size and tumorigenesis by inhibiting cell proliferation and promoting apoptosis. KIBRA [kidney and brain expressed protein] is an upstream regulator of the Hippo-YAP signaling. The role KIBRA plays in mitosis has not been established. We show that KIBRA activates the Aurora kinases during mitosis and KIBRA promotes the phosphorylation of large tumor suppressor 2 by activating Aurora-A. We further show that knockdown of KIBRA causes mitotic abnormalities, including defects of spindle and centrosome formation and chromosome misalignment. The transcriptional co-activator with PDZ-binding motif is a downstream effector of the Hippo tumor suppressor pathway. In the ...


Functional Characterization Of The Roles Of Endocytic Recycling Regulator Ehd1 Using In Vivo And In Vitro Analyses, Priyanka Arya Aug 2015

Functional Characterization Of The Roles Of Endocytic Recycling Regulator Ehd1 Using In Vivo And In Vitro Analyses, Priyanka Arya

Theses & Dissertations

Endocytic recycling is a fundamental cellular process that allows the precise regulation of the membrane components and receptors at the cell surface. Recent studies have established that the C-terminal Eps15 homology domain-containing (EHD) proteins function as key regulators of this process. Four highly-conserved members of the EHD protein family in mammals, EHD1-EHD4, play shared as well as unique roles in endocytic trafficking. Studies presented here demonstrate a critical role of EHD1 in the normal ocular development in mice. Ehd1 knockout mice generated in our laboratory displayed gross ocular phenotypes including the anophthalmia, microphthalmia, and congenital cataracts. Hematoxylin and eosin (H ...


Role Of Macrophages In Muscle Transfection With Pdna/Pluronic Formulation, Vivek Mahajan Aug 2015

Role Of Macrophages In Muscle Transfection With Pdna/Pluronic Formulation, Vivek Mahajan

Theses & Dissertations

Non-ionic amphiphilic block copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), Pluronics, arranged in a tri-block structure PEO-PPO-PEO, have raised a considerable interest in skeletal muscle Gene Therapy. Previous studies have demonstrated that co-administration of Pluronics with naked plasmid DNA (pDNA) by direct i.m. injection enhanced transgene expression not only in muscle but also in distal lymphoid organs (spleen and lymph nodes) and this response was strain-dependent; not observed in athymic (BALB/c nu/nu) mouse; suggesting a role of immune cells in gene transfer to skeletal muscles. Therefore, we first evaluated the role of inflammation ...


Lgr5 Activates Tgfβ Signaling And Suppresses Metastasis In Colon Cancer, Xiaolin Zhou May 2015

Lgr5 Activates Tgfβ Signaling And Suppresses Metastasis In Colon Cancer, Xiaolin Zhou

Theses & Dissertations

Metastasis is the major cause of death in colorectal cancer patients, mainly due to the ineffectiveness of current therapies once metastases begin to form. Further insight into the biology of colorectal cancer metastasis is, therefore, essential in order to gain a greater understanding of this process and ultimately to develop better cancer therapies to prevent or target metastasis. LGR5 is leucine-rich repeat containing G protein-coupled receptor (GPCR) and was discovered as a marker for proliferating adult stem cells in the small intestine. LGR5 and its homologs LGR4 and LGR6 are receptors of R-spondins (RSPOs), which are secreted agonists of canonical ...