MicroRNA miR-155 inhibits bone morphogenetic protein (BMP) signaling and BMP-mediated Epstein-Barr virus reactivation.
MicroRNA miR-155 is expressed at elevated levels in human cancers including cancers of the lung, breast, colon, and a subset of lymphoid malignancies. In B cells, miR-155 is induced by the oncogenic latency gene expression program of the human herpesvirus Epstein-Barr virus (EBV). Two other oncogenic herpesviruses, Kaposi's sarcoma-associated herpesvirus and Marek's disease virus, encode functional homologues of miR-155, suggesting a role for this microRNA in the biology and pathogenesis of these viruses. Bone morphogenetic protein (BMP) signaling is involved in an array of cellular processes, including differentiation, growth inhibition, and senescence, through context-dependent interactions with multiple signaling pathways. Alteration of this pathway contributes to a number of disease states including cancer. Here, we show that miR-155 targets the 3' untranslated region of multiple components of the BMP signaling cascade, including SMAD1, SMAD5, HIVEP2, CEBPB, RUNX2, and MYO10. Targeting of these mediators results in the inhibition of BMP2-, BMP6-, and BMP7-induced ID3 expression as well as BMP-mediated EBV reactivation in the EBV-positive B-cell line, Mutu I. Further, miR-155 inhibits SMAD1 and SMAD5 expression in the lung epithelial cell line A549, it inhibits BMP-mediated induction of the cyclin-dependent kinase inhibitor p21, and it reverses BMP-mediated cell growth inhibition. These results suggest a role for miR-155 in controlling BMP-mediated cellular processes, in regulating BMP-induced EBV reactivation, and in the inhibition of antitumor effects of BMP signaling in normal and virus-infected cells.
Yin
Qinyan
Q
Tulane Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
Wang
Xia
X
Fewell
Claire
C
Cameron
Jennifer
J
Zhu
Hanqing
H
Baddoo
Melody
M
Lin
Zhen
Z
Flemington
Erik K
EK
D001402:B-Lymphocytes / Q000821:virology; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D015398:Signal Transduction; D014775:Virus Activation
D019485:Bone Morphogenetic Proteins; C524942:MIRN155 microRNA, human; D035683:MicroRNAs