p53-Responsive MicroRNAs 192 and 215 Are Capable of Inducing Cell Cycle Arrest

Abstract

microRNAs provide a novel layer of regulation for gene expression by interfering with the stability and/or translation of specific target mRNAs. Overall levels of microRNAs are frequently down-regulated in cancer cells, and reducing general microRNA processing increases cancerogenesis in transgenic models, suggesting that at least some microRNAs might act as effectors in tumor suppression. Accordingly, the tumor suppressor p53 up-regulates miR-34a, a microRNA that contributes to apoptosis and acute senescence. Here, we used array hybridization to find that p53 induces two additional, mutually related clusters of microRNAs, leading to the up-regulation of miR-192, miR-194, and miR-215. The same microRNAs were detected at high levels in normal colon tissue but were severely reduced in many colon cancer samples. On the other hand, miR-192 and its cousin miR-215 can each contribute to enhanced CDKN1A/p21 levels, colony suppression, cell cycle arrest, and cell detachment from a solid support. These effects were partially dependent on the presence of wild-type p53. Antagonizing endogenous miR-192 attenuated 5-fluorouracil-induced accumulation of p21. Hence, miR-192 and miR-215 can act as effectors as well as regulators of p53; they seem to suppress cancerogenesis through p21 accumulation and cell cycle arrest. [Cancer Res 2008;68(24):10094-104]

E2F1-inducible microRNA 449a/b suppresses cell proliferation and promotes apoptosis

“…In contrast, E2F1 induced miR-34a far less efficiently than miR-449a (Supplementary Figure S1B). Conversely, p53 activation by the pharmacological Mdm2 antagonist Nutlin-3a, 29 although capable of inducing miR-34a, 12 failed to increase the levels of miR-449a (Supplementary Figure S1C). miR-449 expression is coupled to its host gene CDC20B and reduced in tumor cells.…”

“…Cultures were maintained for 2 weeks with Blasticidin (10 mg/ml), followed by fixation and staining, as described previously. 12 Flow cytometry. The attached cells combined with floating cells were harvested and fixed in 70% ethanol at 41C.…”

“…10,11 Strikingly, p53 was found to induce the expression of some miRNAs. [12][13][14] Most notably, the miR-34 family of miRNAs contributes to apoptosis on induction by p53. [15][16][17][18][19][20] These findings raise the question whether E2F1 may also induce miRNAs that contribute to apoptosis.…”

Breast Cancer/Stromal Cells Coculture on Polyelectrolyte Films Emulates Tumor Stages and miRNA Profiles of Clinical Samples

“…miRNA-34a has been reported to be downregulated in nonsmall cell lung carcinomas, pancreas tumor cell lines, colon carcinomas and primary neuroblastomas. 76,77 In contrast, Dutta and co-workers observed a high incidence of miRNA-34a overexpression in various tumor types. 78 Consistent with the data of Peurala et al, 75 we detected varying miRNA-34a levels in our coculture platform depending on the source of the cells.…”

(micro)Genomic medicine: microRNAs as therapeutics and biomarkers

“…27 Other miRNAs likely to be part of the p53 pathway are miR-192 and its paralog miR-215, which are induced by p53 and promote G 1 and G 2 arrest in vitro. [28][29][30] Mimics for these miRNAs hold promise in oncology if upon effective delivery to tumors they can induce cell cycle arrest or apoptosis.…”