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The role of poly (ADP-ribose) polymerase-1 in the celluar response to several marine-derived compounds
Descriptive
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Text
TitleInfo
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Title
The role of poly (ADP-ribose) polymerase-1 in the celluar response to several marine-derived compounds
SubTitle
PartName
PartNumber
NonSort
Identifier
ETD_1764
Identifier
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http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000051035
Language
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LanguageTerm
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eng
Genre
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theses
Subject
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(authority = RUETD)
Topic
Cell and Developmental Biology
Subject
(ID = SBJ-2);
(authority = ETD-LCSH)
Topic
Marine organisms--Composition
Subject
(ID = SBJ-3);
(authority = ETD-LCSH)
Topic
Pharmacology
Subject
(ID = SBJ-4);
(authority = ETD-LCSH)
Topic
Animal extracts
Subject
(ID = SBJ-5);
(authority = ETD-LCSH)
Topic
DNA polymerases
Abstract
PARP-1 is a multi-functional protein that is involved in many DNA-dependent genomic processes under normal and pathophysiological conditions. It is well characterized as a DNA damage detector and responds by catalytic production and attachment of polymers of ADP-ribose (PAR) to nuclear protein targets, facilitating the chromatin changes that are a prerequisite to DNA repair. In this study, we tested whether PARP-1 is involved in the cellular response to Yondelis®, Zalypsis®, PSL1, and PSL2, novel chemotherapeutic agents with putative DNA damage- and transcription-targeted activities. We observed a dose-dependent activation of PARP-1 catalytic activity following treatment with all four compounds, while PARP-1 protein levels remained unchanged. Interestingly, cells derived from PARP-1 null mice were significantly sensitized to the agents, yet, with respect to Yondelis®, only moderate DNA damage was observed which was repaired with equal efficiency by both PARP-1 wildtype and PARP-1 null cells. While the mechanism of sensitization is unclear, it is of interest to determine whether inhibition of PARP in human cells could sensitize cells to the four agents. Initial in vivo experiments testing this prediction using MX-1 breast carcinoma xenografts treated with Yondelis® alone or in combination with the PARP-1 inhibitor DIQ, demonstrate an additive effect between these two compounds with regard to tumor volume inhibition and tumor growth delay. However, corresponding in vitro experiments failed to corroborate this observation. The effects of PARP-1 on the transcription of genes impacting drug sensitivity, as well as the cyto-protective role of PARP-1 independent of its catalytic function are of interest to direct future efforts to clarify the mechanism of PARP-1-mediated sensitivity to the four agents. Taken together, these data suggest that PARP-1 plays an important role in the protection of cells to Yondelis®, Zalypsis®, PSL1, and PSL2, and suggest that PARP-1 status may determine the sensitivity or resistance of cells treated with these agents.
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electronic resource
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ix, 53 p. : ill.
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Note
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M.S.
Note
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Includes bibliographical references (p. 45-53)
Note
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by Brijesh B. Patel
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Patel
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Brijesh B.
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Brijesh B. Patel
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Ganesan
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Shridar
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chair
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Advisory Committee
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Shridar Ganesan
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(type = family)
Haimovich
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(type = given)
Beatrice
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internal member
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Advisory Committee
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Beatrice Haimovich
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NamePart
(type = family)
Scotto
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(type = given)
Kathleen
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(authority = RULIB);
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internal member
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Advisory Committee
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Kathleen Scotto
Name
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Rutgers University
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degree grantor
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Graduate School - New Brunswick
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school
OriginInfo
DateCreated
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2009
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2009-05
Location
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NjNbRU
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TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier
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ETD
RelatedItem
(type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier
(type = local)
rucore19991600001
Identifier
(type = doi)
doi:10.7282/T3154H9W
Genre
(authority = ExL-Esploro)
ETD graduate
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The author owns the copyright to this work.
Copyright
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Copyright protected
Availability
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Open
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Non-exclusive ETD license
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Author Agreement License
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I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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4413440
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