miR-15b/16-2 regulates factors that promote p53 phosphorylation and augments the DNA damage response following radiation in the lung [Cell Biology]
August 4th, 2014 by Rahman, M., Lovat, F., Romano, G., Calore, F., Acunzo, M., Bell, E. H., Nana-Sinkam, P.
MicroRNAs (miRNAs) are regulatory RNAs frequently dysregulated in disease and following cellular stress. Investigators have described changes in miR-15b expression following exposure to several stress-inducing anticancer agents including ionizing radiation (IR), etoposide, and hydrogen peroxide. However, the role for miR-15b as a mediator of cellular injury in organs such as the lung has yet to be explored. In this study, we examined miR-15b expression patterns as well as its potential role in DNA damage and repair in the setting of IR exposure. We showed that miR-15b is up-regulated in a dose and time dependent manner in human bronchial epithelial cells (HBEC) following IR. miR-15b expression was highest after 2 hrs. of IR and gradually decreased. Survival rates following IR were also higher in miR-15b/16-2 overexpressing cells. Cell cycle arrest in G2/M phase and increased DNA repair response were observed in IR exposed miR-15b/16-2 stable cells. We observed an up-regulation of components of the ATM/Chek1/p53 pathway in miR-15b/16-2 overexpressing cells after IR. Moreover, a pathway-based PCR expression array of genes demonstrated that miR-15b/16-2 over-expression significantly induced the expression of genes involved in ATM/ATR signaling, apoptosis, cell-cycle and DNA repair pathways. Here, we have demonstrated a novel biological link between miR-15b and DNA damage and cellular protection in lung cells. We identified Wip1 (PPM1D) as a functional target for miR-15b and determined that miR-15b induction of the DNA damage response (DDR) was partially dependent upon suppression of Wip1. Our study suggests that miR-15b/Wip1 could be a potential therapeutic target in radiation induced lung disease.