TAT-RasGAP317-326 requires p53 and PUMA to sensitize tumor cells to genotoxins

Détails

ID Serval
serval:BIB_72E6D50C6000
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
TAT-RasGAP317-326 requires p53 and PUMA to sensitize tumor cells to genotoxins
Périodique
Molecular Cancer Research
Auteur(s)
Michod  D., Widmann  C.
ISSN
1541-7786 (Print)
Statut éditorial
Publié
Date de publication
05/2007
Volume
5
Numéro
5
Pages
497-507
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: May
Résumé
Although chemotherapy has revolutionized cancer treatment, the associated side effects induced by lack of specificity to tumor cells remain a challenging problem. We have previously shown that TAT-RasGAP(317-326),a cell-permeable peptide derived from RasGAP, specifically sensitizes cancer cells to the action of genotoxins. The underlying mechanisms of this sensitization were not defined however. Here, we report that TAT-RasGAP(317-326) requires p53, but not the Ras effectors Akt and extracellular signal-regulated kinase, to mediate its tumor sensitization abilities. The TAT-RasGAP(317-326) peptide, although not modulating the transcriptional activity of p53 or its phosphorylation and acetylation status, nevertheless requires a functional p53 cellular status to increase the sensitivity of tumor cells to genotoxins. Genes regulated by p53 encode proapoptotic proteins, such as PUMA, and cell cycle control proteins, such as p21. The ability of TAT-RasGAP(317-326) to sensitize cancer cells was found to require PUMA but not p21. TAT-RasGAP(317-326) did not affect PUMA levels, however, but increased genotoxin-induced mitochondrial depolarization and caspase-3 activation. These results indicate that TAT-RasGAP(317-326) sensitizes tumor cells by activating signals that intersect with the p53 pathway downstream of, or at the level of, proapoptotic p53 target gene products to increase the activation of the mitochondrial death pathway.
Mots-clé
Acetylation/drug effects Apoptosis/drug effects Apoptosis Regulatory Proteins/*metabolism Cell Line, Tumor Cisplatin/pharmacology Cyclin-Dependent Kinase Inhibitor p21/metabolism Enzyme Activation/drug effects Extracellular Signal-Regulated MAP Kinases/metabolism Gene Products, tat/chemistry/*pharmacology HCT116 Cells Humans MAP Kinase Signaling System/drug effects Mutagens/*pharmacology Neoplasms/metabolism/*pathology Peptides/pharmacology Phosphorylation/drug effects Proto-Oncogene Proteins/*metabolism Proto-Oncogene Proteins c-akt/metabolism Thermodynamics Transcription, Genetic/drug effects Tumor Suppressor Protein p53/genetics/*metabolism ras GTPase-Activating Proteins/chemistry/*pharmacology
Pubmed
Web of science
Open Access
Oui
Création de la notice
24/01/2008 15:43
Dernière modification de la notice
08/05/2019 20:23
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