Item Details

GATA6 Crosstalk Between Insulin Signaling and Tumor Necrosis Factor Alpha-Induced Gene Expression

Chitforoushzadeh, Zeinab
Format
Thesis/Dissertation; Online
Author
Chitforoushzadeh, Zeinab
Advisor
Janes, Kevin
Abstract
Many diseases involve malfunction of several signaling pathways. After close to a century of signaling research, we have access to a wealth of information about many individual signaling pathways. However, in order to take our understanding to the next level, we need to study signaling pathways in the context of each other. These types of systematic studies require simultaneous measurement of multiple entities across several time points. The resulting big and complex data sets can be simplified and decoded by means of computational techniques such as mathematical modeling. The work in my thesis builds upon a prediction from a data-driven statistical model using bioinformatics tools to extract hypotheses. These hypotheses are further tested in vitro by means of molecular biology techniques and pharmacological perturbations. Specifically, the model predicted that an early-phase, Akt-associated signal downstream of insulin repressed a set of transcripts induced by TNF. Through bioinformatics and cell-based experiments, we identified the Akt-repressed signal as glycogen synthase kinase-3 (GSK3)-catalyzed phosphorylation of Ser37 on the long form of the transcription factor GATA6. Phosphorylation of GATA6 on Ser37 promoted its degradation, thereby inhibiting the ability of GATA6 to act as a repressor of transcripts that are induced by TNF and attenuated by insulin. Our analysis showed that insulin-induced signaling activity and TNF-induced transcriptional regulation is integrated through phosphorylation of GATA6L.
Language
English
Date Received
20160730
Published
University of Virginia, Department of Pharmacology, PHD (Doctor of Philosophy), 2016
Published Date
2016-07-31
Degree
PHD (Doctor of Philosophy)
Collection
Libra ETD Repository
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