Mitocondria

Some miRNAs of Therapeutic Interest

The p53 transcriptional network is an important tumor suppressor pathway, as induction of the p53 transcription factor leads to apoptosis and growth arrest in response to DNA damage
and cellular stress. Many tumors have mutations in p53, and the p53 pathway has been a focus for oncology drug development.18-20 The miRNAs miR-34a,b, and c are induced uponactivation of a p53 response and the promoter regions for these miRNAs contain conserved p53 binding sites that are bound by p53.21-24 These studies have confirmed that miR-34 family members cause G1 cell cycle arrest in vitro. Furthermore, miR-34a expression is low in cancer cells of various tissues25 including neuroblastomas,26 and frequently these tumors have deletions that include the mir-34loci.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 G1 and G2 arrest in vitro.28-30 Mimics for these miRNAs hold promise in oncology if upon effective delivery to tumors they
can induce cell cycle arrest or apoptosis.
Another transcription factor, NFB, regulates response to cellular stress, as well as immune andinflammatory responses.31 NFB is highly expressed in some cancer models and there is a
potential causal correlation between NFB-related inflammation and cancer.32 MicroRNA profiling of immune stimulated monocytes revealed that NFB induces transcription of miR-146
and miR-155.33 Genetic manipulations in mice demonstrate that miR-155 regulates cellular differentiation and function of B and Tlymphocytes.34,35 Both miR-146 and miR-155 appear
to promote inflammation and immune response, and overexpression of miR-155 correlates with acute myeloid leukemia36 and B cell lymphomas.37 Recent studies indicate that the miR-155
regulatory pathway is utilized by Kaposi’s sarcoma associated herpesvirus (KSHV), since the virally encoded miR-K12-11 shares seed sequence identity with miR-155, andrepresses a similar set of genes.38,39 Interestingly, prior to the discovery of microRNAs in humans, the noncoding transcript BIC was linked to retrovirally induced lymphoma,40 and it is now known that the BIC transcript is the precursor (i.e., primary transcript) for miR-155.37
Perturbation of miR-146 and miR-155 expression may provide new ways to direct the NFB pathway for therapeutic purposes incancer and immune disease.
Upregulated expression of the transcription factor Myc is associated with many cancer tumor types.41,42 One target of Myc is a cluster of poly-cistronic microRNAs: miR-17, miR-18a,
miR19a, miR20a, miR19b-1, miR-92a-1 (miR-17~92).43,44 The miR-17~92 cluster has two functional paralogs at distinct genomic loci in mammals (i.e., miR-106a~363 and miR-106b~25), however onlymiR-17~92 has broad expression across tissues and is critical for survival in mice.45 Overexpression of miR-17~92 is associated with cancers including large B cell lymphomas and small cell lung cancer,46,47 and experimental perturbation demonstrates that overexpression of these miRNAs can induce cellular proliferation phenotypes similar to those seen by c-myc induction alone.48-50
Completeknockout mice for miR-17~92 exhibit prenatal lethality with embryos significantly smaller than wild type littermates, characterized by hypoplasic lungs and reduced numbers of pre-B cells in liver, all results of increased apoptosis.45 Accordingly, miR-17~92 family members have been shown to target mRNA of known proapoptotic genes such as Bim45 and E2f1.44,51
Accordingly, antagonism of these miRNAsin tumors may have beneficial outcomes.

Many miRNAs are expressed in a very tissue-specific fashion,52,53 suggesting that miRNAs play roles in the development or maintenance of particular tissues. Control of these miRNAs could have applications for treating a spectrum of disorders including those related to metabolism, muscular function and hormone regulation. For example, several miRNAs are...