Title |
Transcriptional targets and protein interactions of NKX2-2 in Ewing sarcoma |
Publication Type |
dissertation |
School or College |
School of Medicine |
Department |
Oncological Sciences |
Author |
Fadul, John Phillip Lorenzo |
Date |
2015-08 |
Description |
Ewing sarcoma is a bone-associated malignancy of children and adolescents caused by EWS/FLI, an oncogenic transcription factor encoded by a chromosomal translocation. EWS/FLI causes massive transcriptional dysregulation. A critical upregulated target, NKX2-2, is a homeodomain transcription factor required for Ewing sarcomagenesis; however, its specific role in this disease is unknown. We addressed this question using a twofold approach. First, using RNA sequencing, we found that NKX2-2 represses genes important for cell adhesion and ECM organization. We also show that it inhibits mesenchymal features of Ewing sarcoma cells: actin stress fiber organization, focal adhesion assembly, cell spreadingâ€"phenocopying EWS/FLI knockdown. NKX2-2-depleted cells also display increased cell adhesion and migration. Finally, we show that NKX2-2 and ZEB2 mediate anti-mesenchymalization and anti-epithelialization programs, respectively, in Ewing sarcoma to keep cells in a partially undifferentiated state. Second, we show that NKX2.2 binds MTG16 in an interaction that is disrupted by Notch. Presumably, these proteins comprise a repressor complex given the proper cellular context. Furthermore, NKX2.2 is capable of oligomerization; interestingly, both heterotypic and homotypic interactions are mediated by the transcriptional activation domain of NKX2.2. While the biological significance of the NKX2.2-MTG16 interaction is currently unknown, we propose that investigating this complex may be tractable in pancreatic β-islet cells. Importantly, defining the transcriptional targets and elucidating the molecular interactions of critical transcription factors in Ewing sarcoma, as well as in other cancers, may more fully define their function. |
Type |
Text |
Publisher |
University of Utah |
Subject MESH |
Bone Neoplasms; Sarcoma, Ewing; RNA-Binding Protein EWS; Translocation, Genetic; Transcription, Genetic; Genes, Homeobox; Biomarkers, Tumor; Homeodomain Proteins; Cell Transformation, Neoplastic; Transcription Factors; Receptors, Notch; Proto-Oncogene Protein c-fli-1; SEER Program |
Dissertation Institution |
University of Utah |
Dissertation Name |
Doctor of Philosophy |
Language |
eng |
Relation is Version of |
Digital version of Transcriptional Targets and Protein Interactions of NKX2-2 in Ewing Sarcoma |
Rights Management |
Copyright © John Phillip Lorenzo Fadul 2015 |
Format |
application/pdf |
Format Medium |
application/pdf |
Format Extent |
5,104,792 bytes |
Source |
Original in Marriott Library Special Collections |
ARK |
ark:/87278/s6cg3w2j |
Setname |
ir_etd |
ID |
1355485 |
Reference URL |
https://collections.lib.utah.edu/ark:/87278/s6cg3w2j |