title: An intronic microRNA links Rb/E2F and EGFR signaling.
abstract: The importance of microRNAs in the regulation of various aspects of biology and disease is well recognized. However, what remains largely unappreciated is that a significant number of miRNAs are embedded within and are often co-expressed with protein-coding host genes. Such a configuration raises the possibility of a functional interaction between a miRNA and the gene it resides in. This is exemplified by the Drosophila melanogaster dE2f1 gene that harbors two miRNAs, mir-11 and mir-998, within its last intron. miR-11 was demonstrated to limit the proapoptotic function of dE2F1 by repressing cell death genes that are directly regulated by dE2F1, however the biological role of miR-998 was unknown. Here we show that one of the functions of miR-998 is to suppress dE2F1-dependent cell death specifically in rbf mutants by elevating EGFR signaling. Mechanistically, miR-998 operates by repressing dCbl, a negative regulator of EGFR signaling. Significantly, dCbl is a critical target of miR-998 since dCbl phenocopies the effects of miR-998 on dE2f1-dependent apoptosis in rbf mutants. Importantly, this regulation is conserved, as the miR-998 seed family member miR-29 repressed c-Cbl, and enhanced MAPK activity and wound healing in mammalian cells. Therefore, the two intronic miRNAs embedded in the dE2f1 gene limit the apoptotic function of dE2f1, but operate in different contexts and act through distinct mechanisms. These results also illustrate that examining an intronic miRNA in the context of its host's function can be valuable in elucidating the biological function of the miRNA, and provide new information about the regulation of the host gene itself.
authors: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors: Mary
authors: M
authors: Truscott
authors: Department of Genetic Engineering & Biotechnology, University of Dhaka, Dhaka, Bangladesh; Department of Experimental and Health Sciences, Barcelona Biomedical Research Park, Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors: Abul B M M K
authors: AB
authors: Islam
authors: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors: James
authors: J
authors: Lightfoot
authors: Department of Experimental and Health Sciences, Barcelona Biomedical Research Park, Universitat Pompeu Fabra (UPF), Barcelona, Spain; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
authors: Núria
authors: N
authors: López-Bigas
authors: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors: Maxim V
authors: MV
authors: Frolov
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D007438:Introns / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D018010:Receptors, Invertebrate Peptide / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors
chemical_list: D029721:Drosophila Proteins; D050684:E2F Transcription Factors; C496298:E2f1 protein, Drosophila; C561805:MIRN11 microRNA, Drosophila; C000595119:MIRN998 microRNA, Drosophila; D035683:MicroRNAs; D018010:Receptors, Invertebrate Peptide; D014157:Transcription Factors; D050721:Proto-Oncogene Proteins c-cbl; C066532:Egfr protein, Drosophila; D066246:ErbB Receptors; C106411:Cbl protein, Drosophila