Background:The mechanism by which Ral GTPases mediate malignant transformation is not well understood. Results: Depletion of Ral leads to increases in ATM kinase p53, Ser-15 phosphorylation, p53 half-life, and p53-dependent expression of p21 WAF . Conclusion: Ral expression is required for maintaining low levels of p53. Significance: Down-regulation of Ral reactivates p53 by enhancing its stability, and this contributes to suppression of malignant transformation.
The regulation of the tumor suppressor p53 by Ral GTPases and its contribution to malignant transformation are not known. Here we demonstrate that the expression of K-Ras, Ral A and Ral B, but not Akt1/2 and c-Raf, is required for maintaining low levels of p53 in human cancer cells that harbor mutant K-Ras and wild type p53. Depletion of Ral A and Ral B increases p53 protein levels by increasing its stability and this results in p53-dependent up regulation of p21waf and mdm2. Furthermore, depletion of Ral A and / or Ral B leads to a p53-dependent decrease in the proportion of cells in the S-phase of the cell cycle, inhibition of anchorage-independent growth and suppression of invasion. Thus, expression of Ral proteins is critical to maintaining low levels of p53, and this appears to be critical to the ability of Ral GTPase to induce malignant transformation.
Citation Format: Awet Tecleab, Xiaolei Zhang, Said M. Sebti. RalGTPase regulation of p53 and its contribution to malignant transformation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 767. doi:10.1158/1538-7445.AM2013-767
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.