Dissertation/Thesis Abstract

Systematic analysis of essential genes reveals new regulators of G protein signaling
by Cappell, Steven D., Ph.D., The University of North Carolina at Chapel Hill, 2010, 162; 3456255
Abstract (Summary)

Heterotrimeric G proteins are molecular switches that respond to a wide range of stimuli including light, neurotransmitters, small molecules and peptides. Due to their role in a variety of physiological responses, it is no surprise that over 50% of drugs modulate G protein signaling pathways. While many drugs function at the level of the G protein-coupled receptor, downstream signaling components are increasingly being investigated as drug targets. Therefore, discovery of new components and regulators will help identify new ways to exploit G protein-coupled signaling pathways for therapeutic utility.

Previous attempts to systematically identify new components of G protein pathways have focused on genome-wide knockout screens including gene-deletion mutants. However, these methods are inherently limited because they exclude the essential genes. In this thesis, we present studies to identify new signaling components by systematically analyzing 870 essential genes using repressible-promoter strains. Specifically, we show that the SCFCdc4 E3 ubiquitin ligase complex regulates G protein turnover and catalyzes ubiquitination of the G protein subunit, Gpa1. Also, we demonstrate that Pik1, a phosphatidylinositol (PtdIns) 4-kinase, regulates the mitogen-activated protein kinase (MAPK) cascade and helps maintain signaling fidelity. These findings reveal the essential-genome as an untapped resource for identifying new components and regulators of signal transduction pathways. Furthermore, work on this thesis has expanded our understanding of G protein signaling networks and could lead to future opportunities for drug discovery.

Indexing (document details)
Advisor: Dohlman, Henrik G.
Commitee: Bankaitis, Vytas A., Graves, Lee M., Johnson, Gary L., Siderovski, David P.
School: The University of North Carolina at Chapel Hill
Department: Pharmacology
School Location: United States -- North Carolina
Source: DAI-B 72/08, Dissertation Abstracts International
Subjects: Pharmacology, Biochemistry
Keywords: Essential genes, G proteins, Ubiquitin
Publication Number: 3456255
ISBN: 978-1-124-65598-7
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