A novel source for miR-21 expression through the alternative polyadenylation of VMP1 gene transcripts

Judit Ribas, Xiaohua Ni, Mark Castanares, Minzhi M. Liu, David Esopi, Srinivasan Yegnasubramanian, Ronald Rodriguez, Joshua T. Mendell, Shawn E. Lupold

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

miR-21 is the most commonly over-expressed microRNA (miRNA) in cancer and a proven oncogene. Hsa-miR-21 is located on chromosome 17q23.2, immediately downstream of the vacuole membrane protein-1 (VMP1) gene, also known as TMEM49. VMP1 transcripts initiate ∼130kb upstream of miR-21, are spliced, and polyadenylated only a few hundred base pairs upstream of the miR-21 hairpin. On the other hand, primary miR-21 transcripts (pri-miR-21) originate within the last introns of VMP1, but bypass VMP1 polyadenylation signals to include the miR-21 hairpin. Here, we report that VMP1 transcripts can also bypass these polyadenylation signals to include miR-21, thus providing a novel and independently regulated source of miR-21, termed VMP1-miR-21. Northern blotting, gene-specific RT-PCR, RNA pull-down and DNA branching assays support that VMP1-miR-21 is expressed at significant levels in a number of cancer cell lines and that it is processed by the Microprocessor complex to produce mature miR-21. VMP1 and pri-miR-21 are induced by common stimuli, such as phorbol-12- myristate-13-acetate (PMA) and androgens, but show differential responses to some stimuli such as epigenetic modifying agents. Collectively, these results indicate that miR-21 is a unique miRNA capable of being regulated by alternative polyadenylation and two independent gene promoters.

Original languageEnglish (US)
Pages (from-to)6821-6833
Number of pages13
JournalNucleic acids research
Volume40
Issue number14
DOIs
StatePublished - Aug 2012

ASJC Scopus subject areas

  • Genetics

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    Ribas, J., Ni, X., Castanares, M., Liu, M. M., Esopi, D., Yegnasubramanian, S., Rodriguez, R., Mendell, J. T., & Lupold, S. E. (2012). A novel source for miR-21 expression through the alternative polyadenylation of VMP1 gene transcripts. Nucleic acids research, 40(14), 6821-6833. https://doi.org/10.1093/nar/gks308