Type of Document	Dissertation
Author	Armstrong, Michaele JoAnn
Author's Email Address	armstrongmichaele@hotmail.com
URN	etd-08012006-143958
Title	Mechanisms of IRF-1 Induced Cancer Growth Inhibition
Degree	Doctor of Philosophy
Program	Human Genetics
School	Graduate School of Public Health
Advisory Committee	Advisor Name Title John H. Yim, M.D. Committee Chair Jack C. Yalowich, Ph.D. Committee Member Lin Zhang, Ph.D Committee Member Robert E. Ferrell, Ph.D. Committee Member
Keywords	Cancer survivin cell cycle arrest apoptosis IRF-1 p21
Date of Defense	2006-08-11
Availability	restricted
Abstract The tumor suppressor IRF-1 has been gaining interest as a mediator of anticancer therapies and its role in mediating apoptosis and cell cycle arrest are currently being elucidated. Through the creation of recombinant adenoviral (Ad-) IRF-1 in our lab, we are in a unique position to study the underlying mechanisms of IRF-1 mediated tumor growth inhibition. First, we will further determine the role of IRF-1 in caspase-mediated apoptosis. Our work will examine the mechanism of IRF-1 activation of initiator caspase 8 and effector caspases 3 and 7 and the role of soluble factors. Our second course of study will delineate the role of IRF-1 mediated cell cycle effects and with a focus on G1 arrest and p21waf1cip1 upregulation. Our initial hypothesis that IRF-1 induces caspase 3/7 mediated apoptosis through a death receptor pathway in conjunction with the secretion of soluble factors in cancer was not supported by results obtained. We found that death ligands were not mediating IRF-1 growth inhibition; however we did find that the caspase cascade was clearly involved. Moreover, we have shown that caspase 8 activity is central in mediating IRF-1 apoptosis. While investigating the intrinsic pathway we made a novel discovery that IRF-1 localizes to the mitochondria. The significance of this finding is still under investigation. Studies of p21 knock down confirmed that IRF-1 utilizes p21 in p53 independent G1 cell cycle arrest. We hypothesized that cell cycle arrest would “protect” the cells from apoptosis but found that p21 up regulation by IRF-1 corresponded to caspase cleavage and that apoptosis was suppressed in our p21 knock down cell lines. We also found that the inhibitor of apoptosis, survivin may account for this effect. Finally, we show that IRF-1 growth inhibitory effects are directed to malignant and not normal breast cells. We show that this too may be linked to survivin which is commonly overexpressed in cancers and suppressed by IRF-1. Greater understanding of the mechanisms of IRF-1 cancer growth inhibition is significant to public health because it may allow better utilization and development of IRF-1 and agents that are mediated by IRF-1 in cancer treatment.
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