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Cellular zinc homeostasis

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TitleInfo
Title
Cellular zinc homeostasis
SubTitle
a regulator of the pharmacodynamics and innate resistance of zinc metallochaperones
Name (type = personal)
NamePart (type = family)
Kogan
NamePart (type = given)
Samuel
DisplayForm
Samuel Kogan
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Bertino
NamePart (type = given)
Joseph
DisplayForm
Joseph Bertino
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = personal)
NamePart (type = family)
Carpizo
NamePart (type = given)
Darren R
DisplayForm
Darren R Carpizo
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Ganesan
NamePart (type = given)
Shridar
DisplayForm
Shridar Ganesan
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Gunderson
NamePart (type = given)
Samuel
DisplayForm
Samuel Gunderson
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
outside member
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
School of Graduate Studies
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2018
DateOther (type = degree); (qualifier = exact)
2018-10
CopyrightDate (encoding = w3cdtf)
2018
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
TP53 is the most commonly mutated gene in cancer; therefore, small molecule restoration of wild type structure and function to mutant p53 (hereafter referred to as “reactivation”) is a highly sought-after goal in cancer therapeutics. Mutations that impair the p53 protein’s ability to bind zinc (zinc deficient mutants) are exceedingly prevalent in cancer. Zinc metallochaperones (ZMCs) are a class of small molecules that reactivate zinc deficient p53 mutants by restoring zinc binding. ZMCs raise intracellular zinc levels by functioning as zinc ionophores, causing mutant p53 to refold properly, which we have termed the “ON” switch. Here we have investigated the cancer cell’s response to this zinc surge and demonstrate that within hours, cellular zinc homeostatic mechanisms normalize zinc levels leading to mutant p53 misfolding and inactivation of the drug, which we have termed the “OFF” switch. This ON/OFF switch imparts a pulsatile nature to the mechanism of ZMCs which indicates that only a brief exposure of a ZMC is necessary for its p53-mediated cell kill. Cell growth inhibition experiments in which we varied the time of exposure to ZMC1 demonstrate an on-target effect in as little as 15 minutes. This switch mechanism is unique in cancer therapeutics and imparts an advantage over other targeted therapeutics in that efficacy can be achieved with minimal exposure which minimizes toxicity and maximizes the therapeutic window. We have extended our understanding of the role of cellular zinc homeostatic mechanisms in ZMC function to serving as a source of innate resistance. HCC1395 is a human triple-negative breast cancer cell line that expresses a zinc-deficient mutant p53 (p53-R175H) but is resistant to ZMC1 withno evidence of refolding of the p53-R175H. We observe that the ZMC1-induced zinc kinetics are markedly reduced when compared to a ZMC1-sensitive cell line. Expression of several cytosolic zinc binding proteins are higher in the resistant cell line, and knockdown of their expression markedly increases the zinc levels in response to ZMC1. Supplementation of ZnCl2 results in a large zinc influx which causes refolding of p53-R175H and sensitizes the cells to ZMC1.Together these data support the hypothesis that cellular zinc homeostatic mechanisms function as an “OFF” switch to regulate the mechanism of ZMCs and also contribute to innate resistance to ZMCs. The latter indicates that high metallothionein levels may serve as a biomarker of resistance to ZMCs.
Subject (authority = RUETD)
Topic
Pharmacology, Cellular and Molecular
Subject (authority = ETD-LCSH)
Topic
Cancer--Treatment
Subject (authority = ETD-LCSH)
Topic
p53 protein
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_9040
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (100 pages) : illustrations
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Note (type = statement of responsibility)
by Samuel Kogan
RelatedItem (type = host)
TitleInfo
Title
School of Graduate Studies Electronic Theses and Dissertations
Identifier (type = local)
rucore10001600001
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier (type = doi)
doi:10.7282/t3-t89p-7725
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Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Kogan
GivenName
Samuel
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2018-05-14 11:48:58
AssociatedEntity
Name
Samuel Kogan
Role
Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
AssociatedObject
Type
License
Name
Author Agreement License
Detail
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.
RightsEvent
Type
Embargo
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2018-10-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2019-05-02
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after May 2nd, 2019.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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Technical

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windows xp
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DateCreated (point = end); (encoding = w3cdtf); (qualifier = exact)
2018-09-28T13:05:08
DateCreated (point = end); (encoding = w3cdtf); (qualifier = exact)
2018-09-28T13:05:08
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