Growth Inhibition by miR-519 via Multiple p21-Inducing Pathways

Author:

Abdelmohsen Kotb1,Srikantan Subramanya1,Tominaga Kumiko1,Kang Min-Ju1,Yaniv Yael2,Martindale Jennifer L.1,Yang Xiaoling1,Park Sung-Soo3,Becker Kevin G.4,Subramanian Murugan5,Maudsley Stuart3,Lal Ashish5,Gorospe Myriam1

Affiliation:

1. Laboratory of Molecular Biology and Immunology, National Institute on Aging, NIH, Baltimore, Maryland, USA

2. Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Baltimore, Maryland, USA

3. Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, Maryland, USA

4. Research Resources Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA

5. National Cancer Institute, NIH, Bethesda, Maryland, USA

Abstract

ABSTRACT The microRNA miR-519 robustly inhibits cell proliferation, in turn triggering senescence and decreasing tumor growth. However, the molecular mediators of miR-519-elicited growth inhibition are unknown. Here, we systematically investigated the influence of miR-519 on gene expression profiles leading to growth cessation in HeLa human cervical carcinoma cells. By analyzing miR-519-triggered changes in protein and mRNA expression patterns and by identifying mRNAs associated with biotinylated miR-519, we uncovered two prominent subsets of miR-519-regulated mRNAs. One subset of miR-519 target mRNAs encoded DNA maintenance proteins (including DUT1, EXO1, RPA2, and POLE4); miR-519 repressed their expression and increased DNA damage, in turn raising the levels of the cyclin-dependent kinase (cdk) inhibitor p21. The other subset of miR-519 target mRNAs encoded proteins that control intracellular calcium levels (notably, ATP2C1 and ORAI1); their downregulation by miR-519 aberrantly elevated levels of cytosolic [Ca 2+ ] storage in HeLa cells, similarly increasing p21 levels in a manner dependent on the Ca 2+ -activated kinases CaMKII and GSK3β. The rises in levels of DNA damage, the Ca 2+ concentration, and p21 levels stimulated an autophagic phenotype in HeLa and other human carcinoma cell lines. As a consequence, ATP levels increased, and the level of activity of the AMP-activated protein kinase (AMPK) declined, further contributing to the elevation in the abundance of p21. Our results indicate that miR-519 promotes DNA damage, alters Ca 2+ homeostasis, and enhances energy production; together, these processes elevate the expression level of p21, promoting growth inhibition and cell survival.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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