• Login
    View Item 
    •   Home
    • UA Faculty Research
    • UA Faculty Publications
    • View Item
    •   Home
    • UA Faculty Research
    • UA Faculty Publications
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of UA Campus RepositoryCommunitiesTitleAuthorsIssue DateSubmit DateSubjectsPublisherJournalThis CollectionTitleAuthorsIssue DateSubmit DateSubjectsPublisherJournal

    My Account

    LoginRegister

    About

    AboutUA Faculty PublicationsUA DissertationsUA Master's ThesesUA Honors ThesesUA PressUA YearbooksUA CatalogsUA Libraries

    Statistics

    Most Popular ItemsStatistics by CountryMost Popular Authors

    A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    KangText.pdf
    Size:
    1.287Mb
    Format:
    PDF
    Description:
    Final Accepted Manuscript
    Download
    Thumbnail
    Name:
    Supporting_Information.pdf
    Size:
    719.5Kb
    Format:
    PDF
    Description:
    Supplemental Data
    Download
    Author
    Kang, Hyun-Jin
    Cui, Yunxi
    Yin, Holly
    Scheid, Amy
    Hendricks, William P. D.
    Schmidt, Jessica
    Sekulic, Aleksandar
    Kong, Deming
    Trent, Jeffrey M.
    Gokhale, Vijay
    Mao, Hanbin
    Hurley, Laurence H.
    Show allShow less
    Affiliation
    Univ Arizona, Coll Pharm
    Univ Arizona, Coll Sci,
    Arizona Canc Ctr
    Issue Date
    2016-10-19
    
    Metadata
    Show full item record
    Publisher
    AMER CHEMICAL SOC
    Citation
    A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters 2016, 138 (41):13673 Journal of the American Chemical Society
    Journal
    Journal of the American Chemical Society
    Rights
    Copyright © 2016 American Chemical Society.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    Activation of human telomerase reverse transcriptase (hTERT) is necessary for limitless replication in tumorigenesis. Whereas hTERT is transcriptionally silenced in normal cells, most tumor cells reactivate hTERT expression by alleviating transcriptional repression through diverse genetic and epigenetic mechanisms. Transcription-activating hTERT promoter mutations have been found to occur at high frequencies in multiple cancer types. These mutations have been shown to form new transcription factor binding-sites that drive hTERT expression, but this model cannot fully account for differences in wild-type (WT) and mutant promoter activation and has not yet enabled a selective therapeutic strategy. Here, we demonstrate a novel mechanism by which promoter mutations activate hTERT transcription, which also sheds light on a unique therapeutic opportunity. Promoter mutations occur in a core promoter region that forms tertiary structures consisting of a pair of G-quadruplexes involved in transcriptional silencing. We show that promoter mutations exert a detrimental effect on the folding of one of these G-quadruplexes, resulting in a nonfunctional silencer element that alleviates transcriptional repression. We have also identified a small drug-like pharmacological chaperone (pharmacoperone) molecule, GTC365, that acts at an early step in the G-quadruplex folding pathway to redirect mutant promoter G-quadruplex misfolding, partially reinstate the correct folding pathway, and reduce hTERT activity through transcriptional repression. This transcription-mediated repression produces cancer cell death through multiple routes including both induction of apoptosis through inhibition of hTERT's role in regulating apoptosis-related proteins and induction of senescence by decreasing telomerase activity and telomere length. We demonstrate the selective therapeutic potential of this strategy in melanoma cells that overexpress, hTERT.
    Note
    Publication Date (Web): September 19, 2016. 12 month embargo.
    ISSN
    0002-7863
    1520-5126
    DOI
    10.1021/jacs.6b07598
    Version
    Final accepted manuscript
    Sponsors
    National Science Foundation [CH-1609514, CHE-1415883]; National Institutes of Health [5R01CA153821, 1R01GM085585]; Stand Up To Cancer Melanoma Research Alliance/Melanoma Dream Team Translational Cancer Research Grant [SU2C-AACR-DT0612]
    Additional Links
    http://pubs.acs.org/doi/abs/10.1021/jacs.6b07598
    ae974a485f413a2113503eed53cd6c53
    10.1021/jacs.6b07598
    Scopus Count
    Collections
    UA Faculty Publications

    entitlement

     
    The University of Arizona Libraries | 1510 E. University Blvd. | Tucson, AZ 85721-0055
    Tel 520-621-6442 | repository@u.library.arizona.edu
    DSpace software copyright © 2002-2017  DuraSpace
    Quick Guide | Contact Us | Send Feedback
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.