Date of Award

9-24-2004

Embargo Period

1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular and Cellular Biology and Pathobiology

Additional Department

Cell Biology and Anatomy

College

College of Graduate Studies

First Advisor

Robin Muise-Helmericks

Second Advisor

Alexander Awgulewitsch

Third Advisor

Makio Ogawa

Fourth Advisor

Demetri D. Spyropoulos

Fifth Advisor

Dennis K. Watson

Abstract

Natural Killer (NK) cells are critical for protection from cancer and infectious disease. The hypothesis that there is a molecular link between IL-2 receptor signaling and Ets1 was investigated. This hypothesis was based on the correlation between an NK-deficient phenotype generated by gene targeting of the Ets1 transcription factor, IL-2 receptor, IL-2 and IL-15, indicating that each of these proteins is required for the proper development and function of NK cells. The findings presented show that both IL-2 and IL-15 induce a post-transcriptional regulation of Ets1 in NK cells. Pharmacological and transient transfection analyses, using a method developed within to express exogenous genes in NK cells, confirm the Ets1 protein synthesis is regulated through a MEK>ERK1>MNK1>eIF4E signaling pathway in NK cells that is initiated by activation of the common IL-2 receptor subunis β and γ. This IL-2 induction of Ets1 protein synthesis is potentially controlled by cis-acting elements located within both the 5' and/or 3'UTRs. An evaluation of the potential functions of Ets1 in NK cells by the assessment of specific target genes in NK cells is discussed and a novel target gene confirmed using siRNA directed against Ets1.

Rights

All rights reserved. All rights reserved. Copyright is held by the author.

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