Journal
JOURNAL OF CELL BIOLOGY
Volume 182, Issue 3, Pages 509-517Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200801079
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Funding
- National Institutes of Health [R01CA70896, R01CA75503, R01CA86072, R01CA107382]
- National Institutes of Health Cancer Center Core [P30CA56036]
- Dr. Ralph and Marian C. Falk Medical Research Trust
- Pennsylvania Department of Health
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Decreased expression of specific microRNAs ( miRNAs) occurs in human tumors, which suggests a function for miRNAs in tumor suppression. Herein, levels of the miR-17-5p/miR-20a miRNA cluster were inversely correlated to cyclin D1 abundance in human breast tumors and cell lines. MiR-17/20 suppressed breast cancer cell proliferation and tumor colony formation by negatively regulating cyclin D1 translation via a conserved 3 ' untranslated region miRNA-binding site, thereby inhibiting serum-induced S phase entry. The cell cycle effect of miR-17/20 was abrogated by cyclin D1 siRNA and in cyclin D1-deficient breast cancer cells. Mammary epithelial cell-targeted cyclin D1 expression induced miR-17-5p and miR-20a expression in vivo, and cyclin D1 bound the miR-17/20 cluster promoter regulatory region. In summary, these studies identify a novel cyclin D1/miR-17/20 regulatory feedback loop through which cyclin D1 induces miR- 17-5p/miR-20a. In turn, miR-17/20 limits the proliferative function of cyclin D1, thus linking expression of a specific miRNA cluster to the regulation of oncogenesis.
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