This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Michod, D. Articles by Widmann, C. Search for Related Content PubMed PubMed Citation Articles by Michod, D. Articles by Widmann, C.

---

Signaling and Regulation

TAT-RasGAP_317-326 Requires p53 and PUMA to Sensitize Tumor Cells to Genotoxins

Department of Physiology and Department of Cell Biology and Morphology, Lausanne University, Lausanne, Switzerland

Requests for reprints: Christian Widmann, Department of Physiology, Lausanne University, Rue du Bugnon 7/9, 1005 Lausanne, Switzerland. Phone: 41-21-692-5123; Fax: 41-21-692-5255. E-mail: Christian.Widmann{at}unil.ch

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. (Mol Cancer Res 2007;16(1):497–507)