Date of Award

2020-01-01

Degree Name

Doctor of Philosophy

Department

Biological Sciences

Advisor(s)

Robert A. Kirken

Abstract

In the United States, pediatric leukemia has the second-highest cancer mortality rate in Hispanic children, especially Acute Lymphocytic Leukemia (ALL). While treatment of ALL has improved overall the five-year survival rate of ~90 %, not everyone has benefited. Twenty percent of them will experience relapse, and from these, 30 - 50 % will die. Unfortunately, the cause behind these dreadful statistics is poorly understood due to the complex etiology of this disease. Thereby, it is essential to identify potential oncogenic proteins that promote ALL so that new strategies can be developed to diagnose and treat this cancer. Whole Exome Sequencing (WES) coupled with OncoMiner Pipeline sorting identified five Single Nucleotide Polymorphisms (SNPâ??s) on the Mitogen-Activated Protein Kinase Kinase 3 (MEK3) (MAP2K3) gene in El Paso del Norte ALL cancer patient library. MAP2K3 mutations were recreated using site-directed mutagenesis and transfected into HEK293 cells to study their impact on cell function. Three mutations were located within the kinase domain and two others located to the MEK3 amino domain. Transfection of HEK293 cells revealed these variants impact protein stability by inducing increased degradation of MEK3. Data shown here further suggest that they serve to block the auto-phosphorylation of MEK3, and loss of kinase activity towards p38. MEK3 is responsible for the activation of MAPK p38 to mediate growth-inhibitory and pro-apoptotic signals. Thus, inhibition of p38 activity through enhanced degradation of MEK3 mutants renders this pathway nonfunctional contributing to tumor cell proliferation. These findings indicate MEK3 represents a therapeutic target for controlling and treating ALL.

Language

en

Provenance

Received from ProQuest

File Size

86 pages

File Format

application/pdf

Rights Holder

Yoshira Marie Ayala-Marin

Available for download on Thursday, January 20, 2022

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