Biochemistry, Biophysics, and Structural Biology Commons^™

Role Of Non-Coding Rna Nc4 In Mll And Cyp33 Mediated Regulation Of Hoxc8, Jessica Arvindbhai Solanki

Dissertations

MLL or Mixed Lineage Leukemia gene is clinically known for its involvement in genetic translocation with more than 70 different partners identified each giving rise to a highly leukemogenic fusion protein. With a poor prognosis of MLL related leukemia, an investigation into its role during hematopoiesis has been a very active field of research. In order to design strategies to combat the MLL leukemia, it becomes essential to delineate the molecular mechanisms behind the function of MLL wild type protein. Wild type MLL is a transcriptional maintenance protein from the Trithorax Group (TrxG) that resides in complex with other chromatin …

Role Of Notch Signaling In T Cell Polarization, Shilpa Keerthivasan

Dissertations

The differentiation of CD4+ T cells to different effector lineages in response to pathogenic stimuli is the core of the adaptive immune system. One of the effector subsets recently discovered is Thelper 17 (Th17) and it plays a predominant role in autoimmune diseases and inflammatory disorders.

In my thesis, I aimed to study the role of Notch cell surface receptors in Th17 differentiation. Using in vitro Th17 differentiation assays of human naïve CD4+ T cells, I have shown that Notch signaling, particularly Notch1, plays a crucial role in Th17 polarization. By using pharmacological inhibitors and specific knockdown of Notch1, I …

The Specific Role Of The Mll Cxxc Domain In Mll Fusion Protein Function, Laurie Ellen Risner

Dissertations

The MLL gene was first identified because it is involved in chromosome translocations which produce novel fusion proteins that cause leukemia. The CXXC domain of MLL is a cysteine rich DNA binding domain with specificity for binding unmethylated CpG-containing DNA. The CXXC domain is retained in oncogenic MLL fusions, and is absolutely required for the fusions to cause leukemia. This project explored the role of the CXXC domain by introducing structure-informed point mutations within the MLL CXXC domain that disrupt DNA binding, and by performing domain swap experiments in which different CXXC domains from other proteins, including DNMT1, CGBP and …

Repression Of Protein Kinase C Delta In Human Squamous Cell Carcinomas By Ras, Fyn And Nf-Kappa B Signaling, Vipin Yadav

Dissertations

The delta isoform of Protein Kinase C (PKC-delta) is widely expressed in many normal tissues, including epidermal keratinocytes, and has a critical role in UV-induced apoptosis. However, PKC-delta is frequently lost in chemically or UV-induced mouse skin tumors, as well as in human cutaneous squamous cell carcinomas (SCC). Furthermore, re-expression of PKC-delta in human SCC lines is sufficient to induce apoptosis and suppress tumorigenicity, making PKC-delta a potential tumor suppressor gene for SCCs. The objective of this dissertation is to investigate the mechanism of PKC-delta loss in human SCCs.

To determine the mechanism of PKC-delta loss in human SCCs, we …

Notch-1 Specifically Activates Erk1/2 In Multiple Breast Cancer Subtypes, Allison Schuyler Rogowski

Master's Theses

Notch-1 is a cell fate regulatory protein and a potent breast oncogene. Notch-1 and its ligand Jagged-1 are over-expressed in human breast cancers that are associated with poor overall survival (Reedijk, Odorcic et al. 2005). Deregulated Notch signaling may contribute to tumorigenesis by increasing proliferation, inhibiting differentiation, and preventing apoptosis (Miele, Golde et al. 2006). The mitogen-activated protein kinase (MAPK) pathway is a critical cell signaling pathway that has been implicated in the development and progression of cancer (Hanahan and Weinberg 2000). Four major MAPK pathways are involved in both cell growth and apoptosis. The regulation of these pathways is …

Wee1 Is A Biological Target Of The Mir-17-92 Cluster In Leukemia, Sonia Susan Olikara

Master's Theses

MicroRNAs are noncoding RNAs that bind to the 3' untranslated region of their mRNA targets, which causes downregulation of target gene expression. Previous studies have shown that the miR-17-92 cluster, which encodes six miRNAs, is overexpressed in leukemias arising from chromosomal translocations of the Mixed Lineage Leukemia (MLL) gene. In the present study, prediction algorithms identified WEE1, a kinase that inhibits cell cycle progression, as a possible target of five of the six miRNAs. Through luciferase reporter assays, we found that miR-17, miR-20a, and miR-18a specifically target nucleotides 465 to 487 of the 3' UTR of WEE1, while miR-19a and …