Regulation of Cellular Growth and Differentiation by MicroRNAs -21 and -451
Patrick, David M.
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MicroRNAs are small RNAs approximately 20-24 nucleotides in length that are conserved throughout evolution. MicroRNA genes are transcribed by RNA polymerase II and are processed both in the nucleus and the cytoplasm from longer precursor RNAs. Functionally, microRNAs interact with Argonaute proteins and guide the formation of a complex with messenger RNAs by Watson-Crick base-pair formation between the microRNA and mRNA. This association stimulates the formation of the microRNA-RNA-induced silencing complex which, upon association with essential adaptor molecules such as GW182, recruits transcriptional repressors and mRNA destabilizers. Essential developmental processes such as embryonic stem cell differentiation and cardiovascular development have been shown to be dependent upon microRNAs. MicroRNAs also participate in a variety of disease processes including tumorigenesis and cardiovascular disease. MicroRNA-451 (miR-451) is regulated during erythrocyte terminal differentiation. The expression of miR-451 is restricted to late erythrocyte precursors and terminally differentiated erythrocytes. We therefore hypothesized that miR-451 plays a role in terminal erythroid differentiation. Deletion of miR-451 in mice results in a terminal erythroid differentiation defect both embryonically and in adulthood. These animals display a reduction in hematocrit and an inability to sustain a high erythropoietic rate. Transient inhibition of miR-451 results in the same defect. Transcript profiling of miR-451-/- erythroblasts revealed upregulation of 14-3-3ξ, a molecule implicated in the regulation of hematopoiesis. Knockdown of 14-3-3ξ with shRNA in miR-451-/- erythroblasts attenuates the differentiation defect. These data show the essential role of miR-451 repression of 14-3-3ξ during terminal erythrocyte differentiation. Finally, the potent effect of miR-451 inhibition on erythrocyte production suggests that this strategy may be efficacious for the treatment of polycythemia vera, a myeloproliferative neoplasm characterzed by excessive erythrocyte production. Inhibition of miR-451 in a mouse model of PV significantly reduces disease burden. MicroRNA-21 (miR-21) is regulated in a variety of both human and mouse models of disease. MiR-21 has been widely reported as a driver of tumorigenesis and is consistently upregulated in cardiac remodeling. It has been suggested that miR-21 plays a protective role during cardiac hypertrophy, however, an opposing report suggests that miR-21 inhibition is beneficial in a mouse model of cardiac remodeling. We therefore hypothesized that miR-21 played an essential role in cardiac hypertrophy and remodeling. Deletion of miR-21 in mice resulted in no observable phenotype. MiR-21-/- displayed cardiac remodeling, cardiac stress-responsive gene activation, and reduction in cardiac function in response to four cardiac stress models: thoracic aortic constriction, angiotensin II infusion, calcineurin overexpression, and myocardial infarction. Moreover, inhibition of miR-21 with an LNA-modified miR-21 inhibitor did not modify cardiac remodeling. Finally, inducible genetic deletion of miR-21 did not modify the cardiac response to TAC. These data do not support a role for miR-21 in cardiac disease, however, further analyses of miR-21-/- mice show that these animals are protected from non-small-cell lung cancer (NSCLC). Furthermore, miR-21-/- mouse embryonic fibroblasts are sensitized to doxorubicin-induced apoptosis. These data suggest that inhibition of miR-21 will be efficacious in the treatment of NSCLC while having minimal effects on other tissue types.