Double-Duty MicroRNA: Destroy and Decoy

Science Signaling  09 Mar 2010:
Vol. 3, Issue 112, pp. ec71
DOI: 10.1126/scisignal.3112ec71

Patients with a chromosomal translocation called the Philadelphia chromosome produce an oncogenic fusion protein called BCR/ABL, which leads to chronic myeloid leukemia (CML). BCR/ABL stimulates the activity of an RNA binding protein called hnRNP E2, which inhibits the translation of the mRNA encoding the transcription factor C/EBPα, which is important in the differentiation of white blood cells. The interaction between hnRNP E2 and the C/EBPα-encoding mRNA involves a cytosine (C)–rich region of mRNA’s 5'-untranslated region. In cells from patients in “blast crisis” (CML-BC), as opposed to those from the “chronic phase” (CML-CP), hnRNP E2 is abundant and inhibits C/EBPα production. Eiring et al. screened for microRNAs (miRNAs) that were decreased in CML-BC cells compared with CMP-CP cells and focused on miR-328 because it has a C-rich element similar to that in the mRNA for C/EBPα. Multiple assays showed that miR-328 interacted with hnRNP E2 and competed with C/EPBα-encoding mRNA for binding to hnRNP E2. Unexpectedly, the complexes between hnRNP E2 and miR-328 did not contain proteins involved in mRNA silencing, and the interaction of hnRNP E2 and miR-328 did not require the miR-328 “seed” sequence that is involved in miRNA-mRNA interactions. Forced expression of miR-328 or a seed-mutated form in BCR/ABL-transformed cells rescued differentiation of these cells. The abundance of C/EBPα was increased by forced expression of miR-328, and this was not associated with increased abundance of the C/EBPα-encoding mRNA or a decrease in the abundance of hnRNP E2, which suggests a nonsilencing function of miR-328. The ability of miR-328 to promote C/EBPα translation was confirmed with an in vitro reticulolysate assay and in a cellular assay. Mice injected with BCR/ABL blasts with or without the forced expression of miR-328 showed no change in survival, but animals injected with miR-328–expressing cells showed a phenotype resembling CML-CP, whereas the other animals injected with blasts lacking forced expression of miR-328 showed a CML-BC phenotype. Finally, the authors showed that miR-328 acted as an mRNA silencing miRNA to inhibit the production of the kinase PIM1, which is important for BCR/ABL cell survival. Thus, miR-328 is a double-duty miRNA, acting as both a competitive inhibitor of a translation-inhibiting RNA binding protein (hnRNP E2) to promote protein synthesis and as an RNA silencer to prevent protein synthesis (see Beitzinger and Meister for commentary).

A. M. Eiring, J. G. Harb, P. Neviani, C. Garton, J. J. Oaks, R. Spizzo, S. Liu, S. Schwind, R. Santhanam, C. J. Hickey, H. Becker, J. C. Chandler, R. Andino, J. Cortes, P. Hokland, C. S. Huettner, R. Bhatia, D. C. Roy, S. A. Liebhaber, M. A. Caligiuri, G. Marcucci, R. Garzon, C. M. Croce, G. A. Calin, D. Perrotti, miR-328 functions as an RNA decoy to modulate hnRNP E2 regulation of mRNA translation in leukemic blasts. Cell 140, 652–665 (2010). [Online Journal]

M. Beitzinger, G. Meister, MicroRNAs: From decay to decoy. Cell 140, 612–614 (2010). [Online Journal]