Epstein-Barr Virus Proteins EBNA3A and EBNA3C Together Induce Expression of the Oncogenic MicroRNA Cluster miR-221/miR-222 and Ablate Expression of Its Target p57

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A relatively unbiased screen of human microRNAs (miRs) revealed that in EBV-transformed B cells, a miR cluster, miR-221/miR-222, that is frequently up-regulated in cancer, is induced by the latent EBV only if the viral nuclear proteins EBNA3A and EBNA3C are both expressed. The same two EBV proteins silence a tumour-suppressor miR cluster miR-143/miR-145. The induction of miR-221/miR-222 results from the activation of a long non-coding primary RNA (pri-miR) via long-range chromatin looping between enhancer elements that bind EBNA3A and EBNA3C and the transcription start site of the pri-miR. A well-established target of miR-221/miR-222 is the cyclin-dependent kinase (CDK) inhibitor p57KIP2, which, because it can inactivate various CDKs, can inhibit cell proliferation—but might have additional functions in B cells. Since EBNA3A and EBNA3C also cooperate to repress the expression of at least two other inhibitors of CDKs (p16INK4a and p15INK4b), this implies a degree of functional redundancy in the deregulation of cell cycle checkpoints by latent EBV. This study has shown for the first time that this capacity to reduce expression of multiple cell cycle inhibitors results not only from direct repression of protein-encoding genes, but also the activation of a long non-coding RNA and cluster of oncogenic miRs.

Vyšlo v časopise: Epstein-Barr Virus Proteins EBNA3A and EBNA3C Together Induce Expression of the Oncogenic MicroRNA Cluster miR-221/miR-222 and Ablate Expression of Its Target p57. PLoS Pathog 11(7): e32767. doi:10.1371/journal.ppat.1005031
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005031

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