Biochemistry, Biophysics, and Structural Biology Commons^™

Regulation Of Cxcr4 Intracellular Trafficking By Ubiquitin, Justine Elizabeth Kennedy

Dissertations

G protein-coupled receptor (GPCR) sorting into the degradative pathway is important for attenuating signaling. Perturbations in this process can manifest in a variety of diseases. Upon agonist activation of the chemokine receptor CXCR4, a GPCR, it is rapidly ubiquitinated, internalized to endosomes and sorted for degradation in lysosomes via the endosomal sorting complex required for transport (ESCRT) pathway. This process culminates in attenuation of CXCR4 signaling. CXCR4 overexpression and increased CXCR4 signaling have been associated with several pathologies including immune deficiency disorders and over 23 cancers. Yet the mechanisms governing the regulation of CXCR4 signaling remain elusive.

CXCR4 is ubiquitinated …

Study Of Escherichia Coli Adp-Glucose Pyrophosphorylase Catalysis: Investigating Critical Roles Of Conserved Arg32 And Lys42 Residues, Angela Lynn Mahaffey

Dissertations

Carbohydrates have been most notable as energy sources for mammals, bacteria (glycogen) and plants (starch) – and in many other species. As such the biosynthesis of carbohydrates is essential to the sustainability of many forms of life, on earth. Adenosine-‘5-diphosphate glucose pyrophosphate (ADP-Glc pyrophosphorylase; ADP-Glc PPase) is the allosterically controlled “first committed step” in both the biosynthetic pathways of starch (~25% amylose and ~75% amylopectin, in plants and algae) and glycogen (in bacteria), preceding the starch/glycogen synthase reaction. By catalyzing the following reaction, ATP + α –D-Glc-1P ADP-Glc + PPi , ADP-Glc PPase functions as the primary enzyme in the …

The Mir-17-92 Cluster Contributes To Mll Leukemia Development Through The Repression Of The Meis1 Competitor Pknox1, Yousaf Anwar Mian

Dissertations

Mixed lineage leukemias have a relatively poor prognosis and arise as a result of translocations between the MLL gene and one of multiple partner genes. Downstream targets of MLL are aberrantly upregulated and include the developmentally important HOX genes and MEIS1, as well as multiple miRNAs, including the miR-17-92 cluster and miR-196b. Here I utilize custom anti-miRNA oligonucleotides to examine the contribution of specific miRNAs to MLL leukemias both as individual miRNAs and in cooperation with other miRNAs. Combinatorial treatment with antagomirs against miR-17 and miR-19a of the miR-17-92 cluster dramatically reduces colony forming ability of MLL-fusion containing cell lines …

The Endosomal Sorting Complex Required For Transport Pathway Mediates Chemokine Receptor Cxcr4 Akt Signaling By Promoting Lysosomal Degradation Of Mtor Antagonist Deptor, Rita Ramkaran Verma

Dissertations

The chemokine receptor CXCR4 is a member of the G protein-coupled receptor (GPCR) family. The cognate ligand for CXCR4 is the C-X-C chemokine known as CXCL12. The CXCL12/CXCR4 signaling axis is essential for a number of developmental processes including organogenesis, vascularization of the GI tract and hematopoiesis. Dysregulated CXCR4 signaling is also implicated in a variety of pathological conditions such as WHIM (Warts, Hypogammaglobunemia, Infections and myelokathexis) syndrome, cardiovascular disease and cancer. Despite its role in several pathologies, the molecular mechanisms mediating CXCR4 signaling are not completely understood. Upon CXCL12 binding to CXCR4, several signaling pathways are activated including the …

Eliminating Acute Myeloid Leukemia Stem Cells By Targeting The Niche Microenviromnent: Co-Inhibition Of Tnf/Il1- Jnk And Nf-Κb, Andrew Volk

Dissertations

Leukemia Stem Cells (LSCs) from Acute Myeloid Leukemia (AML) require the activity of the transcription factor NF-kB to maintain stemness and drive tumor formation. Blocking NF-kB can preferentially eliminate LSCs in vitro with minimal effects on healthy Hematopoietic Stem and Progenitor Cells (HSPCs), making NF-kB a compelling target for anti-leukemia therapies. However, blocking NF-kB in vivo can only extend survival for a short period of time before transplanted mice succumb to the disease. I propose this is due to components of the in vivo niche supporting LSC survival and compensating for the inhibition of NF-kB.

I observed patients with partially …

Structure And Molecular Mechanism Of A Plp/Gaba Dependent Transcription Regulator Gabr, Rui Wu

Dissertations

GabR is a member of the MocR/GabR subfamily of the GntR family of bacterial transcription regulators. It regulates the metabolism of γ-aminobutyric acid (GABA), an important nitrogen and carbon source in many bacteria. The crystal structures reported here show that this protein has evolved from the fusion of a type I aminotransferase and a winged helix-turn-helix (wHTH) DNA binding protein to form a chimeric protein that adopts a dimeric head-to-tail configuration. The pyridoxal 5′-phosphate (PLP)-binding regulatory domain of GabR is therefore an example of a coenzyme playing a role in transcription regulation rather than in enzymatic catalysis. Our structural and …