Cell and Developmental Biology Commons^™

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 long been …

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 G_{2 …}

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 Cbl-Family Ubiquitin Ligases As Critical Negative Regulators Of T Cell Activation And Functions, Benjamin Goetz

Theses & Dissertations

Adaptive T cell immunity is essential for defense against foreign antigens and immune surveillance against cancer. Tight regulation of T cell activation is required to avoid autoimmunity to self-antigens or protracted inflammation after foreign antigens are cleared. Incomplete or inappropriate stimulation leads to an active shutdown of T cell activation called anergy. The Casitas B-lineage Lymphoma (CBL)-family of ubiquitin ligases (E3s) are essential negative regulators of T cell activation that impinge on thymic selection as well as anergy induction programs. Single gene studies show that CBL is critical during T cell development while CBL-B plays an essential role in peripheral …

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 …

Exploration Into The Functional Impact Of Muc1 On The Formation And Regulation Of Transcriptional Complexes Containing Ap-1 And P53, Ryan L. Hanson

Theses & Dissertations

The transmembrane glycoprotein MUC1 is aberrantly expressed in the majority of pancreatic ductal adenocarcinoma cases and promotes tumor progression by engaging in morphogenetic signaling through its cytoplasmic tail. Furthermore, MUC1 can translocate to the nucleus and function as a transcriptional co-regulator in conjunction with transcriptional complexes containing activator protein-1 (AP-1) and p53. The specificity of these interactions are thought to rely on specific patterning of post-translational modifications within the cytoplasmic tail of MUC1.

Within this dissertation, we examined how MUC1 influences the formation and activity of these transcription factors and the resulting impact on tumor progression and metastasis. In our …

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

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 recovery, …

The Role Of Dna Methyltransferases In Normal And Malignant Hematopoiesis, Staci Haney

Theses & Dissertations

DNA methylation is an epigenetic modification that regulates gene transcription. The addition of a methyl group to cytosine is catalyzed by a family of enzymes known as DNA methyltransferases (Dnmts). The three catalytically active Dnmts in humans and mice are Dnmt1, Dnmt3a, and Dnmt3b. DNA methylation is clinically relevant, as aberrations in the methylation landscape are a hallmark of nearly all human cancers. Cancer methylomes are typically characterized by genome wide hypomethylation and regional specific hypermethylation, both of which have been linked to alterations in gene expression. In order to understand the contribution of epimutations to the development of hematological …

The Role Of Ada3 Overexpression In Proliferation Through Enhancing Myc Expression, Nicolas I. Griffin

Theses & Dissertations

Breast cancer is a heterogeneous disease that is the second leading cause of cancer related deaths in women. Cancer is defined as abnormally heightened proliferation. In order for gene transcription and eventual translation to occur to drive the cell cycle to generate more cells, DNA must be uncoiled from nucleosomes by histone acetylation complexes. One of the key evolutionarily conserved components of these HAT complexes is alteration/deficiency in activation 3 (ADA3). In addition to the role in histone acetylation, this protein also functions as a coactivator for nuclear hormone receptors. Recent findings indicated that nuclear Ada3 correlates with ER+ breast …

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 …

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 …

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 …

Exploitation Of The Ligand-Binding Properties Of The Mannose 6-Phosphate/Insulin-Like Growth Factor Ii (Igf-Ii) Receptor To Inhibit Igf-Ii-Dependent Growth Of Cancer Cells, Megan Zavorka Thomas

Theses & Dissertations

The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) is a multifunctional, type I transmembrane receptor that is a member of the P-type lectin family. A large, extracytoplasmic (EC) region of the M6P/IGF2R binds various ligands, allowing the receptor to regulate multiple biological functions, including the role as a tumor suppressor. Two major classes of ligands, M6P-glycosylated (i.e. any proteins that bear M6P due to post-translational modification in the trans-Golgi network (TGN)) and non-glycosylated (i.e., the mitogen insulin-like growth factor II (IGF-II)), bind within distinct regions of the EC of the receptor and are trafficked to the lysosome. The M6P/IGF2R as …

Recurrent Mutations Of T-Cell Receptor And Co-Stimulatory Signaling Proteins In Peripheral T-Cell Lymphomas, Joseph Rohr

Theses & Dissertations

Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of mature T-cell neoplasms with a poor prognosis. Recently, mutations in TET2 and other epigenetic modifiers as well as RHOA have been identified in these diseases, particularly in angioimmunoblastic T-cell lymphoma (AITL). CD28 is the major co-stimulatory receptor in T-cells which, upon binding ligand, induces sustained T-cell proliferation and cytokine production when combined with T-cell receptor stimulation, through many signaling molecules including VAV1. This thesis identifies recurrent mutations in CD28 in PTCLs, as well as mutations in VAV1. Two residues of CD28 – D124 and T195 – were recurrently mutated in 11.3% …

Role Of Ecdysoneless In Erbb2/Her2 Mediated Breast Oncogenesis, Shalis A. Ammons

Theses & Dissertations

Breast cancer is the second leading cause of cancer related deaths in women in the United States. The human Epidermal Growth Factor 2 (ErbB2) gene amplification and/or receptor overexpression subtype of breast cancer accounts for 25% of all breast cancers. A crucial regulator of the ErbB2 signaling pathway is the heat shock protein 90 (Hsp90) and its interacting protein complex. One such complex is the R2TP/Prefoldin-like complex that is composed of four proteins, RUVBL1, RUVBL2, PIH1D1, and RPAP3 and seven prefoldin-like proteins. This complex has been shown to be involved in telomere elongation, ribosome biogenesis, protein stability; etc. We and …

Molecular Mechanisms Regulating Myc And Pgc1Β Expression In Colon Cancer, Jamie L. Mccall

Theses & Dissertations

Identification and characterization of pathways specific to tumor cell survival, but absent in normal tissues, provide opportunities to develop effective cancer therapies with reduced toxicity to the patient. Kinase suppressor of Ras 1 (KSR1) is required for the survival of colorectal cancer (CRC) cells, but dispensable in normal cells. Using KSR1 as a reference standard, we identified EPH (erythropoietin-producing hepatocellular carcinoma) receptor (EPHB4) as a KSR1 functional analog.

We show here that, like KSR1, EPHB4 is aberrantly overexpressed in human CRC cells and selectively required for their survival. Both KSR1 and EPHB4 support tumor cell survival by promoting the expression …