Growth differentiation factor-15 encodes a novel microRNA 3189 that functions as a potent regulator of cell death

Abstract

According to the latest version of miRBase, approximately 30% of microRNAs (miRNAs) are unique to primates, but the physiological function of the vast majority remains unknown. In this study, we identified miR-3189 as a novel, p53-regulated, primate-specific miRNA embedded in the intron of the p53-target gene GDF15. Antagonizing miR-3189 increased proliferation and sensitized cells to DNA damage-induced apoptosis, suggesting a tumor suppressor function for endogenous miR-3189. Identification of genome-wide miR-3189 targets revealed that miR-3189 directly inhibits the expression of a large number of genes involved in cell cycle control and cell survival. In addition, miR-3189 downregulated the expression of multiple p53 inhibitors resulting in elevated p53 levels and upregulation of several p53 targets including p21 (CDKN1A), GADD45A and the miR-3189 host gene GDF15, suggesting miR-3189 auto-regulation. Surprisingly, miR-3189 overexpression in p53-/-cells upregulated a subset of p53-targets including GDF15, GADD45A, and NOXA, but not CDKN1A. Consistent with these results, overexpression of miR-3189 potently induced apoptosis and inhibited tumorigenicity in vivo in a p53-independent manner. Collectively, our study identified miR-3189 as a novel, primate-specific miRNA whose effects are mediated by both p53-dependent and p53-independent mechanisms. miR-3189 may, therefore, represent a novel tool that can be utilized therapeutically to induce a potent proapoptotic effect even in p53-deficient tumors.

Long noncoding RNAs in the p53 network

“…Transcriptional regulation of protein‐coding genes by p53 is very well documented in literature . In addition, others and we have shown that several miRNAs are direct targets of p53 and function as downstream effectors of p53 . More recently, specific lncRNAs have been identified as p53 targets and some of these have been shown to function in p53 signaling.…”

Long Noncoding RNA PURPL Suppresses Basal p53 Levels and Promotes Tumorigenicity in Colorectal Cancer

“…In response to stress such as DNA damage, p53 directly activates the transcription of a myriad of protein-coding genes that control a wide variety of cellular processes, including cell cycle arrest, apoptosis and senescence (Bieging and Attardi, 2012, Riley et al, 2008, Beckerman and Prives, 2010). We and others have shown that p53 also directly upregulates several microRNAs including miR-34a and miR-3189 , which, in turn, suppress gene expression downstream of p53 (Chang et al, 2007, Lal et al, 2011, Hermeking, 2012, Jones et al, 2015, Raver-Shapira et al, 2007). More recently, we and others have demonstrated specific functions of a number of p53-regulated lncRNAs, including lincRNA-p21 , PANDA , DINO , PINT , PR-lncRNA-1 , LED , linc-475, NEAT1 and PINCR (Huarte et al, 2010, Dimitrova et al, 2014, Hung et al, 2011, Marin-Bejar et al, 2013, Sanchez et al, 2014, Leveille et al, 2015, Melo et al, 2016, Schmitt et al, 2016, Adriaens et al, 2016, Mello et al, 2017, Chaudhary et al, 2017).…”

Diabetes mellitus related biomarker: The predictive role of growth-differentiation factor-15

“…Several animal studies were determined the positive effect of over-expressed GDF-15 on cell viability independently related to encoding a novel microRNA 3189 that functions as a potent ATF3 mediated regulator of cell death [19]. Inversely, GDF15 probably is able to bind with matrix metalloproteinase 26 that facilitate the pro-apoptotic effect of this cytokine [20].…”