A comprehensive in vivo screen for anti-apoptotic miRNAs indicates broad capacities for oncogenic synergy
| Autor: | Fernando Bejarano, Wu-Min Deng, Eric C. Lai, Joshua W. Hagen, Chih-Hsuan Chang, Kailiang Sun |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Programmed cell death
Mutant Gene Expression Apoptosis Computational biology Biology Eye Article law.invention 03 medical and health sciences 0302 clinical medicine law microRNA Animals Drosophila Proteins Gene Regulatory Networks Eye Proteins Molecular Biology Gene 030304 developmental biology 0303 health sciences Cell Death Gene Expression Profiling Tumor Suppressor Proteins Neuropeptides fungi Cell Biology Phenotype MicroRNAs Drosophila melanogaster Gene Expression Regulation Cancer cell Suppressor 030217 neurology & neurosurgery Developmental Biology Genetic screen |
| Zdroj: | Dev Biol |
| ISSN: | 0012-1606 |
| DOI: | 10.1016/j.ydbio.2021.02.010 |
| Popis: | microRNAs (miRNAs) are ~21–22 nucleotide (nt) RNAs that mediate broad post-transcriptional regulatory networks. However, genetic analyses have shown that the phenotypic consequences of deleting individual miRNAs are generally far less overt compared to their misexpression. This suggests that miRNA deregulation may have broader phenotypic impacts during disease situations. We explored this concept in the Drosophila eye, by screening for miRNAs whose misexpression could modify the activity of pro-apoptotic factors. Via unbiased and comprehensively in vivo phenotypic assays, we identify an unexpectedly large set of miRNA hits that can suppress the action of pro-apoptotic genes hid and grim. We utilize secondary assays to validate that a subset of these miRNAs can inhibit irradiation-induced cell death. Since cancer cells might seek to evade apoptosis pathways, we modeled this situation by asking whether activation of anti-apoptotic miRNAs could serve as “second hits”. Indeed, while clones of the lethal giant larvae (lgl) tumor suppressor are normally eliminated during larval development, we find that diverse anti-apoptotic miRNAs mediate the survival of lgl mutant clones in third instar larvae. Notably, while certain anti-apoptotic miRNAs can target apoptotic factors, most of our screen hits lack obvious targets in the core apoptosis machinery. These data highlight how a genetic approach can reveal distinct and powerful activities of miRNAs in vivo, including unexpected functional synergies during disease or cancer-relevant settings. |
| Databáze: | OpenAIRE |
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