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

M. F. Jones, X. Ling Li, Murugan Subramanian, Svetlana A. Shabalina, T. Hara, Y. Zhu, J. Huang, Y. Yang, L. M. Wakefield, K. V. Prasanth, A. Lal

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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.

Original languageEnglish
Pages (from-to)1641-1653
Number of pages13
JournalCell Death and Differentiation
Volume22
Issue number10
DOIs
Publication statusPublished - 9 Oct 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Jones, M. F., Ling Li, X., Subramanian, M., Shabalina, S. A., Hara, T., Zhu, Y., Huang, J., Yang, Y., Wakefield, L. M., Prasanth, K. V., & Lal, A. (2015). Growth differentiation factor-15 encodes a novel microRNA 3189 that functions as a potent regulator of cell death. Cell Death and Differentiation, 22(10), 1641-1653. https://doi.org/10.1038/cdd.2015.9