Ral GTPase down regulation stabilizes and reactivates p53 to inhibit malignant transformation [Signal Transduction]

September 10th, 2014 by Tecleab, A., Zhang, X., Sebti, S. M.

Ral GTPases are critical effectors of Ras, yet the molecular mechanism by which they induce malignant transformation is not well understood. In this manuscript, we found the expression of K-Ras, RalB, and sometimes RalA, but not AKT1/2 and c-Raf, to be required for maintaining low levels of p53 in human cancer cells that harbor mutant K-Ras and wild-type p53. Down-regulation of K-Ras, RalB, and sometimes RalA, increases p53 protein levels and results in a p53-dependent up-regulation of the expression of p21waf. KRas, RalA, and RalB depletion increases p53 stability as demonstrated by ATM kinase activation, increased Ser-15 phosphorylation, and a significant (up to 6-fold) increase in p53 half-life. Furthermore, depletion of K-Ras and RalB inhibits anchorage-independent growth and invasion and interferes with cell cycle progression in a p53-dependent manner. Depletion of RalA inhibits invasion in a p53-dependent manner. Thus, expression of K-Ras and RalB, and possibly RalA proteins is critical to maintaining low levels of p53, and downregulation of these GTPases reactivates p53 by significantly enhancing its stability, and this contributes to suppression of malignant transformation.