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

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

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Messenger RNA
DNA Damage
Growth
Cyclin-Dependent Kinase Inhibitor p21
Carcinoma
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Proteins
AMP-Activated Protein Kinases
MicroRNAs
HeLa Cells
Transcriptome
Cell Survival
Homeostasis
Phosphotransferases
Down-Regulation
Adenosine Triphosphate
Maintenance
Cell Proliferation
Calcium
Phenotype

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Abdelmohsen, K., Srikantan, S., Tominaga, K., Kang, M-J., Yaniv, Y., Martindale, J. L., ... 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

Growth Inhibition by miR-519 via Multiple p21-Inducing Pathways. / Abdelmohsen, Kotb; Srikantan, Subramanya; Tominaga, Kumiko; Kang, Min-Ju; Yaniv, Yael; Martindale, Jennifer L.; Yang, Xiaoling; Park, Sung Soo; Becker, Kevin G.; Subramanian, Murugan; Maudsley, Stuart; Lal, Ashish; Gorospea, Myriam.

In: Molecular and Cellular Biology, Vol. 32, No. 13, 01.07.2012, p. 2530-2548.

Research output: Contribution to journalArticle

Abdelmohsen, K, Srikantan, S, Tominaga, K, Kang, M-J, Yaniv, Y, Martindale, JL, Yang, X, Park, SS, Becker, KG, Subramanian, M, Maudsley, S, Lal, A & Gorospea, M 2012, 'Growth Inhibition by miR-519 via Multiple p21-Inducing Pathways', Molecular and Cellular Biology, vol. 32, no. 13, pp. 2530-2548. https://doi.org/10.1128/MCB.00510-12
Abdelmohsen K, Srikantan S, Tominaga K, Kang M-J, Yaniv Y, Martindale JL et al. Growth Inhibition by miR-519 via Multiple p21-Inducing Pathways. Molecular and Cellular Biology. 2012 Jul 1;32(13):2530-2548. https://doi.org/10.1128/MCB.00510-12
Abdelmohsen, Kotb ; Srikantan, Subramanya ; Tominaga, Kumiko ; Kang, Min-Ju ; Yaniv, Yael ; Martindale, Jennifer L. ; Yang, Xiaoling ; Park, Sung Soo ; Becker, Kevin G. ; Subramanian, Murugan ; Maudsley, Stuart ; Lal, Ashish ; Gorospea, Myriam. / Growth Inhibition by miR-519 via Multiple p21-Inducing Pathways. In: Molecular and Cellular Biology. 2012 ; Vol. 32, No. 13. pp. 2530-2548.
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