Author's Department/Program
Biology and Biomedical Sciences: Human and Statistical Genetics
Language
English (en)
Date of Award
5-24-2010
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Chair and Committee
Howard McLeod
Abstract
Cancer is a leading cause of human death, and it is fundamentally attributable to dysfunctional cell signaling. The PI3K/AKT/mTOR pathway is an important pro-growth intracellular signaling cascade that is often inappropriately activated in a wide array of cancers. Efforts to develop anticancer drugs have therefore focused, in part, on identifying PI3K/AKT/mTOR pathway inhibitors. However, patient response to some such inhibitors is mixed, with some patients experiencing a paradoxical activation of the pathway following treatment. It is therefore necessary to better understand the nature of the PI3K/AKT/mTOR pathway and how it varies in different individuals. The work presented here used cell lines from families to measure the activity of three PI3K/AKT/mTOR pathway members: AKT1, p70S6K and 4E-BP1) in a variety of contexts, including under baseline cell growth conditions and in response to treatment with different PI3K/AKT/mTOR pathway inhibitors. Traditional genetic analyses were used to identify pathway activation phenotypes that were influenced by genetic variation, and genomic regions harboring variation were identified. A new tool for ranking candidate genes was developed and used to select promising genes within these regions for follow-up. Genotyping and association tests of SNPs in these genes identified four variants that were associated with two baseline PI3K/AKT/mTOR pathway activation phenotypes. These represent the first studies to find genetic variants that influence post-translational protein modifications. In addition, the identified SNPs may shed light on normal pathway function as well as new mechanisms for pathway inhibition.
DOI
https://doi.org/10.7936/K7RN35V1
Recommended Citation
Hutz, Janna, "Genetic Analysis of the PI3K/AKT/mTOR Signaling Pathway" (2010). All Theses and Dissertations (ETDs). 887.
https://openscholarship.wustl.edu/etd/887
Comments
Permanent URL: http://dx.doi.org/10.7936/K7RN35V1