PRIMA-1 reactivates mutant p53 by covalent binding to the core domain.

2.50
Hdl Handle:
http://hdl.handle.net/10146/115654
Title:
PRIMA-1 reactivates mutant p53 by covalent binding to the core domain.
Authors:
Lambert, Jeremy M. R.; Gorzov, Petr; Veprintsev, Dimitry B.; Soderqvist, Maja; Segerback, Dan; Bergman, Jan; Fersht, Alan R.; Hainaut, Pierre; Wiman, Klas G.; Bykov, Vladimir J. N.
Abstract:
Restoration of wild-type p53 expression triggers cell death and eliminates tumors in vivo. The identification of mutant p53-reactivating small molecules such as PRIMA-1 opens possibilities for the development of more efficient anticancer drugs. Although the biological effects of PRIMA-1 are well demonstrated, little is known about its molecular mechanism of action. We show here that PRIMA-1 is converted to compounds that form adducts with thiols in mutant p53. Covalent modification of mutant p53 per se is sufficient to induce apoptosis in tumor cells. These findings might facilitate the design of more potent and specific mutant p53-targeting anticancer drugs.
Citation:
Cancer Cell 2009, 15 (5):376-388
Journal:
Cancer Cell
Issue Date:
5-May-2009
URI:
http://hdl.handle.net/10146/115654
DOI:
10.1016/j.ccr.2009.03.003
PubMed ID:
19411067
Additional Links:
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WWK-4W6XRRG-6&_user=1843694&_coverDate=05%2F05%2F2009&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_acct=C000055040&_version=1&_urlVersion=0&_userid=1843694&md5=436fcb826cc30c57c647bbd3b5b66fd2&searchtype=a
Type:
Article
Language:
en
ISSN:
1878-3686
Sponsors:
This work was supported by the Swedish Cancer Society (Cancerfonden), Cancerfo¨ reningen, Karolinska Institutet, Magn. Bergvalls Stiftelse, and the EU 6th framework program (FP6).
Appears in Collections:
Articles

Full metadata record

DC FieldValue Language
dc.contributor.authorLambert, Jeremy M. R.en
dc.contributor.authorGorzov, Petren
dc.contributor.authorVeprintsev, Dimitry B.en
dc.contributor.authorSoderqvist, Majaen
dc.contributor.authorSegerback, Danen
dc.contributor.authorBergman, Janen
dc.contributor.authorFersht, Alan R.en
dc.contributor.authorHainaut, Pierreen
dc.contributor.authorWiman, Klas G.en
dc.contributor.authorBykov, Vladimir J. N.en
dc.date.accessioned2010-11-16T14:50:14Z-
dc.date.available2010-11-16T14:50:14Z-
dc.date.issued2009-05-05-
dc.identifier.citationCancer Cell 2009, 15 (5):376-388en
dc.identifier.issn1878-3686-
dc.identifier.pmid19411067-
dc.identifier.doi10.1016/j.ccr.2009.03.003-
dc.identifier.urihttp://hdl.handle.net/10146/115654-
dc.description.abstractRestoration of wild-type p53 expression triggers cell death and eliminates tumors in vivo. The identification of mutant p53-reactivating small molecules such as PRIMA-1 opens possibilities for the development of more efficient anticancer drugs. Although the biological effects of PRIMA-1 are well demonstrated, little is known about its molecular mechanism of action. We show here that PRIMA-1 is converted to compounds that form adducts with thiols in mutant p53. Covalent modification of mutant p53 per se is sufficient to induce apoptosis in tumor cells. These findings might facilitate the design of more potent and specific mutant p53-targeting anticancer drugs.en
dc.description.sponsorshipThis work was supported by the Swedish Cancer Society (Cancerfonden), Cancerfo¨ reningen, Karolinska Institutet, Magn. Bergvalls Stiftelse, and the EU 6th framework program (FP6).en
dc.language.isoenen
dc.relation.urlhttp://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WWK-4W6XRRG-6&_user=1843694&_coverDate=05%2F05%2F2009&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_acct=C000055040&_version=1&_urlVersion=0&_userid=1843694&md5=436fcb826cc30c57c647bbd3b5b66fd2&searchtype=aen
dc.subjectNeoplasmsen
dc.subjectAntineoplastic Agentsen
dc.subjectAza Compoundsen
dc.subjectMutationen
dc.subjectApoptosisen
dc.subjectProtein Bindingen
dc.subjectTumor Suppressor Protein p53en
dc.subjectHumansen
dc.subjectAnimalsen
dc.subject.meshAnimals-
dc.subject.meshAntineoplastic Agents-
dc.subject.meshApoptosis-
dc.subject.meshAza Compounds-
dc.subject.meshBicyclo Compounds, Heterocyclic-
dc.subject.meshCell Line, Tumor-
dc.subject.meshDrug Design-
dc.subject.meshHumans-
dc.subject.meshMice-
dc.subject.meshMutation-
dc.subject.meshNeoplasms-
dc.subject.meshProtein Binding-
dc.subject.meshProtein Structure, Tertiary-
dc.subject.meshTumor Suppressor Protein p53-
dc.titlePRIMA-1 reactivates mutant p53 by covalent binding to the core domain.en
dc.typeArticleen
dc.identifier.journalCancer Cellen

Related articles on PubMed

All Items in ECNIS-NIOM are protected by copyright, with all rights reserved, unless otherwise indicated.