Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.26.3 (RNase III)
 1,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

microRNAs (miRNAs) play integral roles in diverse processes including tumorigenesis. miRNA gene loci are often found in close conjunction, and such clustered miRNA genes are transcribed from a common promoter to generate polycistronic primary transcript. The primary transcript (pri-miRNA) is then processed by two RNase III proteins to release the mature miRNAs. Although it has been speculated that the miRNAs in the same cluster may play related biological functions, this has not been experimentally addressed. Here we report that the miRNAs in two clusters (miR-106b approximately 93 approximately 25 and miR-222 approximately 221) suppress the Cip/Kip family members of Cdk inhibitors (p57(Kip2), p21(Cip1) and p27(Kip1)). We show that miR-25 targets p57 through the 3'-UTR. Furthermore, miR-106b and miR-93 control p21 while miR-222 and miR-221 regulate both p27 and p57. Ectopic expression of these miRNAs results in activation of Cdk2 and facilitation of G1/S phase transition. Consistent with these results, both clusters are abnormally upregulated in gastric cancer tissues compared to the corresponding normal tissues. Ectopic expression of miR-222 cluster enhanced tumor growth in the mouse xenograft model. Our study demonstrates the functional associations between clustered miRNAs and further implicates that effective cancer treatment may require a combinatorial approach to target multiple oncogenic miRNA clusters.
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PMID:Functional links between clustered microRNAs: suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer. 1915 41

Dicer is an RNase III enzyme essential for the maturation of the majority of microRNAs. Recent studies have revealed downregulation or hemizygous loss of Dicer in many tumor models and demonstrated that suppressing Dicer activity enhances tumorigenic activities of lung and breast cancer cells, which support Dicer as a haploinsufficient tumor suppressor in these cancer models. Surprisingly, we found that knocking down Dicer expression suppresses the growth and tumorigenic capacity of human prostate cancer cell lines, but enhances migratory capacities of some prostate cancer cell lines. Dicer is upregulated in human prostate cancer specimens, but lower Dicer expression portends a shorter time to recurrence. Complete ablation of Dicer activity in a Pten null mouse model for prostate cancer significantly halts tumor growth and progression, demonstrating that microRNAs have a critical role in maintaining cancer cell fitness. In comparison, hemizygous loss of Dicer in the same model also reduces primary tumor burden, but induces a more locally invasive phenotype and causes seminal vesicle obstruction at high penetrance. Disrupting Dicer activity leads to an increase in apoptosis and senescence in these models, presumably through upregulation of P16/INK4a and P27/Kip1. Collectively, these results highlight a pleotropic role of Dicer in tumorigenesis that is not only dosage-dependent but also tissue context-dependent.
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PMID:A dosage-dependent pleiotropic role of Dicer in prostate cancer growth and metastasis. 2385 98