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.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-08012006-143958 |
| Date | 25 September 2006 |
| Creators | Armstrong, Michaele JoAnn |
| Contributors | Robert E. Ferrell, Ph.D., John H. Yim, M.D., Jack C. Yalowich, Ph.D., Lin Zhang, Ph.D |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-08012006-143958/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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