Genetic Analysis of the PI3K/AKT/mTOR Signaling Pathway

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.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biology and Biomedical Sciences: Human and Statistical Genetics

Year dc:date.available

2010

Author dc:creator

• Hutz, Janna

Contributors dc:contributor

• Howard McLeod

• Biology
• Genetics
• Bioinformatics
• Molecular
• AKT
• candidate genes
• cell signaling
• mTOR
• PI3K

Language dc:language

English (en)

DOI

https://doi.org/10.7936/K7RN35V1

OAI identifier oai:identifier

oai:openscholarship.wustl.edu:etd-1886