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

Kotb Abdelmohsen, Subramanya Srikantan, Kumiko Tominaga, Min Ju Kang, Yael Yaniv, Jennifer L. Martindale, Xiaoling Yang, Sung Soo Park, Kevin G. Becker, Murugan Subramanian, Stuart Maudsley, Ashish Lal, Myriam Gorospea

Research output: Contribution to journalArticle

44 Citations (Scopus)

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 [Ca2+] storage in HeLa cells, similarly increasing p21 levels in a manner dependent on the Ca2+-activated kinases CaMKII and GSK3β. The rises in levels of DNA damage, the Ca2+ 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 Ca2+ homeostasis, and enhances energy production; together, these processes elevate the expression level of p21, promoting growth inhibition and cell survival.

Original languageEnglish
Pages (from-to)2530-2548
Number of pages19
JournalMolecular and Cellular Biology
Volume32
Issue number13
DOIs
Publication statusPublished - 1 Jul 2012
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Abdelmohsen, K., Srikantan, S., Tominaga, K., Kang, M. J., Yaniv, Y., Martindale, J. L., Yang, X., Park, S. S., Becker, K. G., Subramanian, M., Maudsley, S., Lal, A., & Gorospea, M. (2012). Growth Inhibition by miR-519 via Multiple p21-Inducing Pathways. Molecular and Cellular Biology, 32(13), 2530-2548. https://doi.org/10.1128/MCB.00510-12