All ETDs from UAB

Advisory Committee Chair

Christopher D Willey

Advisory Committee Members

Donald J Buchsbaum

Jessy S Deshane

Jan Novak

Chad Steele

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

In this study, we investigated the role MARCKS's Effector Domain plays in lung and brain cancer biology. Initially, we identified that MARCKS was present in a range of lung cancer histologies including: squamous cell, adenocarcinoma, and normal lung tissues among others. In addition, lung adenocarcinoma patients with a mutation in the MARCKS gene correlated with decreased survival as determined by The Cancer Genome Atlas. In vitro studies identified that the phosphorylation status of MARCKS's Effector Domain was able to influence lung cancer radiation sensitivity. When MARCKS's Effector Domain was in a non-phosphorylated state, A549 lung cancer cell lines experienced increased radiation sensitivity and prolonged double strand DNA breaks. Furthermore, using a peptide mimic of the Effector Domain decreased changes in cellular processes suggesting that the Effector Domain may potentially be a sight for therapeutic intervention. Additionally, we observed MARCKS to translocate to the nucleus in Glioblastoma multiforme (GBM) cell lines and co-localize with nuclear PIP2. The positive lysine rich Effector Domain is believed to contain the nuclear localization sequence. When the Effector Domain of MARCKS was deleted, MARCKS was not able to enter the nucleus and PIP2 levels decreases compared to wild-type MARCKS cells. We also observed changes in gene expression when the Effector Domain was deleted. Collectively the information presented here identifies novel functions for the Effector Domain of MARCKS along with expanding our understanding of lung and brain cancer biology.

Share

COinS