Author's School

Graduate School of Arts & Sciences

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.

Comments

Permanent URL: http://dx.doi.org/10.7936/K7RN35V1

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