Graduation Date

Fall 2018

Document Type

Thesis

Program

Master of Science degree with a major in Biology

Committee Chair Name

Dr. Amy Sprowles

Committee Chair Affiliation

HSU Faculty or Staff

Second Committee Member Name

Dr. Jenny Cappuccio

Second Committee Member Affiliation

HSU Faculty or Staff

Third Committee Member Name

Dr. Jacob Varkey

Third Committee Member Affiliation

HSU Faculty or Staff

Fourth Committee Member Name

Dr. Bruce O'Gara

Fourth Committee Member Affiliation

HSU Faculty or Staff

Subject Categories

Biology

Abstract

Glioblastoma is an incurable, aggressive, and highly invasive type of brain tumor that harbors tumor initiating cells characterized by disrupted polarized cell divisions. A cell polarity gene lethal (2) giant larvae 1 (Lgl1) has been implicated in gliomas and is a tumor suppressor initially identified in Drosophila with roles in proliferation. The loss of Lgl1 in Drosophila activates the MAPK protein kinase JNK and the Ras pathway and therefore its downstream kinase ERK, a transcription factor modulator. Furthermore, when Lgl1 is knocked out in mice, a phenotype similar to glioma is seen. Loss of the human form of Lgl1, Hugl1, and increases in c-Jun, an oncogene and JNK target, has been associated with glioma in humans. Additionally, the protooncogene transcription factor c-Myc is documented in glioma to directly correlate to tumor grade and an increase in an analogous form, d-Myc, in Drosophila has been shown to promote survival of Lgl mutants through a Ras mechanism. Here we sought to determine if the cancer properties associated with loss of Lgl in mice and humans are related to changes in MAPK signaling. To accomplish this, murine neural progenitor cells from the subventricular zone of mice with a Lgl1 knockout were cultured in vitro. These cells were plated adherently and characterized for changes in phosphorylation states of MAPK proteins ERK, JNK and p38 as well as two protooncogene MAPK downstream targets, c-Jun and c-Myc. In addition, to understand if MAPK phosphorylation is related to proliferation we characterized the proliferation rates of these cells in the presence of chemical inhibitors of p38 and ERK’s upstream activating kinase MEK. Differential expression patterns were observed in MAPK proteins and their downstream targets associated with the loss of Lgl1, under standard conditions and with the treatment of DMSO as a drug vehicle control and chemical inhibitors of p38 and MEK. Additionally, it was found that the loss of Lgl1 in neurosphere culture slightly increased growth and under adherent conditions this effect was not seen, however, changes did occur in the presence of p38 and MEK inhibitors. This supports previous data and signifies the importance of MAPK pathway in cancer phenotypes and beginning to characterize the role of the Lgl1 protein in the mouse.

Citation Style

Cell Journal

Share

 
COinS