Gained in Translation?

Abstract

Rajasekhar et al. used gene expression profiling to compare the effect of oncogenic Ras and Akt signaling on total cellular mRNA and polysomal mRNA and discovered that the immediate effects of signaling through these two pathways on recruitment of specific existing mRNAs to polysomes were far greater than on transcription. Glioblastoma, a highly malignant form of brain cancer, is frequently characterized by increased activity of Ras and Akt; moreover, combined activation of Ras and Akt signaling pathways in glial progenitor cells promotes glioblastoma formation. Rajasekhar used mouse glial progenitor cells expressing constitutively active K-Ras, constitutively active Akt, or both, in combination with small molecule inhibitors of these signaling pathways, to investigate their effects on translational efficiency. Microarray analysis of total cellular mRNA indicated that, of 12,488 genes screened, fewer than 20 genes showed a greater than threefold change in mRNA levels after 2 hours' blockade of Akt or Ras signaling. In contrast, a screen of mRNA associated with polysomes (purified with sucrose gradients) revealed a decrease in the polysome association of hundreds of mRNAs by a factor greater than 3 in response to Akt or Ras blockade, with levels of many changing by a factor greater than 10. Among mRNAs identified as showing changes in polysome association in response to both activation of Ras and Akt signaling and pharmacological inhibition of either pathway were many implicated in oncogenic signaling pathways, as well as many known transcription factors. Thus, the authors propose that the oncogenic effects of Ras and Akt signaling may initially arise predominantly from changes in mRNA translation. V. K. Rajasekhar, A. Viale, N. D. Socci, M. Wiedmann, X. Hu, E. C. Holland, Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. Mol. Cell 12 , 889-901 (2003). [Online Journal]