The miR-34 family in cancer and apoptosis

Hermeking, Heiko

doi:10.1038/cdd.2009.56

Cited by 1,095 publications

(970 citation statements)

References 67 publications

(92 reference statements)

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“…miR-34a, the most extensively studied p53-regulated miRNA, is involved in positive feedback loops with p53 by repressing the p53 inhibitors SIRT1 47 and HDM4, 11 but several studies suggest that its effects, unlike those of miR-3189-3p, depend on the presence of wild-type p53. 11,12,48 Our results indicate that miR-3189-3p also mediates a positive feedback loop in which p53 activation is sustained by downregulation of the known p53 inhibitors HDAC1 and HDAC3. 33,49,50 We found that miR-3189-3p knockdown increases cell death following DNA damage.…”

Section: Discussionmentioning

confidence: 70%

Growth differentiation factor-15 encodes a novel microRNA 3189 that functions as a potent regulator of cell death

Jones

Mahadevan

et al. 2015

Cell Death Differ

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According to the latest version of miRBase, approximately 30% of microRNAs (miRNAs) are unique to primates, but the physiological function of the vast majority remains unknown. In this study, we identified miR-3189 as a novel, p53-regulated, primate-specific miRNA embedded in the intron of the p53-target gene GDF15. Antagonizing miR-3189 increased proliferation and sensitized cells to DNA damage-induced apoptosis, suggesting a tumor suppressor function for endogenous miR-3189. Identification of genome-wide miR-3189 targets revealed that miR-3189 directly inhibits the expression of a large number of genes involved in cell cycle control and cell survival. In addition, miR-3189 downregulated the expression of multiple p53 inhibitors resulting in elevated p53 levels and upregulation of several p53 targets including p21 (CDKN1A), GADD45A and the miR-3189 host gene GDF15, suggesting miR-3189 auto-regulation. Surprisingly, miR-3189 overexpression in p53-/-cells upregulated a subset of p53-targets including GDF15, GADD45A, and NOXA, but not CDKN1A. Consistent with these results, overexpression of miR-3189 potently induced apoptosis and inhibited tumorigenicity in vivo in a p53-independent manner. Collectively, our study identified miR-3189 as a novel, primate-specific miRNA whose effects are mediated by both p53-dependent and p53-independent mechanisms. miR-3189 may, therefore, represent a novel tool that can be utilized therapeutically to induce a potent proapoptotic effect even in p53-deficient tumors.

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Section: Discussionmentioning

confidence: 70%

Growth differentiation factor-15 encodes a novel microRNA 3189 that functions as a potent regulator of cell death

Jones

Mahadevan

et al. 2015

Cell Death Differ

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“…MiR-34 family, which is composed of miR-34a, miR-34b and miR-34c, modulates cell cycle progression, senescence and apoptosis [6,21,22]. MiR-34a is highly expressed in normal tissues, like testis, lung, adrenal gland and spleen.…”

Section: Discussionmentioning

confidence: 99%

TBHP-induced oxidative stress alters microRNAs expression in mouse testis

Fatemi

Sanati

Shamsara

et al. 2014

J Assist Reprod Genet

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Purpose Reactive oxygen species (ROS) and oxidative stress is one of the main reasons of male infertility. MicroRNAs (miRNAs) regulate multiple intracellular processes. Alterations in miRNAs expression may occur in different conditions and diseases. In this study, the effect of oxidative stress induced by tertiary-butyl hydroperoxide (TBHP) on the expression of candidate miRNAs in mouse testis was investigated.Methods After determining median lethal dose (LD 50 ), TBHP was intraperitoneally (ip) injected at the dilution of 1:10 LD 50 into the adult male mice for 2weeks, and then testis tissues were removed in order to assay the ROS level. Total RNA was extracted and the expression of five miRNAs was quantified by reverse transcription-real time polymerase chain reaction (RT-qPCR).Results The flow cytometry analysis showed a significant increase in ROS level in testis. The expression of three out of five selected miRNAs, including miR-34a, miR-181b and miR-122a, showed some degrees of changes following exposure to oxidative stress. These miRNAs are involved in antioxidant responses, inflammation pathway and spermatogenesis arrest. Conclusions In conclusion, TBHP alters the miRNA expression profile of testis which might play a potential role in oxidative and antioxidative responses and spermatogenesis.

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“…24 Members of the miR-34 family have been suggested as critical regulators in regulation of cancer cell apoptosis and cell cycle arrest. 16,25,26 It has been recently reported that suppression of somatic cell reprogramming into pluripotent cells by miR-34a was due to their repression of pluripotency genes, 27 implying that miR-34a could have an important role in stem cell differentiation.…”

Section: S Ir T 1 a C T A 2 T A G Lnmentioning

confidence: 99%

Upregulated sirtuin 1 by miRNA-34a is required for smooth muscle cell differentiation from pluripotent stem cells

Zhang

Wen

et al. 2014

Cell Death Differ

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microRNA-34a (miR-34a) and sirtuin 1 (SirT1) have been extensively studied in tumour biology and longevity/aging, but little is known about their functional roles in smooth muscle cell (SMC) differentiation from pluripotent stem cells. Using well-established SMC differentiation models, we have demonstrated that miR-34a has an important role in SMC differentiation from murine and human embryonic stem cells. Surprisingly, deacetylase sirtuin 1 (SirT1), one of the top predicted targets, was positively regulated by miR-34a during SMC differentiation. Mechanistically, we demonstrated that miR-34a promoted differentiating stem cells' arrest at G0/G1 phase and observed a significantly decreased incorporation of miR-34a and SirT1 RNA into Ago2-RISC complex upon SMC differentiation. Importantly, we have identified SirT1 as a transcriptional activator in the regulation of SMC gene programme. Finally, our data showed that SirT1 modulated the enrichment of H3K9 tri-methylation around the SMC gene-promoter regions. Taken together, our data reveal a specific regulatory pathway that miR-34a positively regulates its target gene SirT1 in a cellular context-dependent and sequence-specific manner and suggest a functional role for this pathway in SMC differentiation from stem cells in vitro and in vivo.

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The miR-34 family in cancer and apoptosis

Cited by 1,095 publications

References 67 publications

Growth differentiation factor-15 encodes a novel microRNA 3189 that functions as a potent regulator of cell death

Growth differentiation factor-15 encodes a novel microRNA 3189 that functions as a potent regulator of cell death

TBHP-induced oxidative stress alters microRNAs expression in mouse testis

Upregulated sirtuin 1 by miRNA-34a is required for smooth muscle cell differentiation from pluripotent stem cells

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