title: Mei-P26 mediates tissue-specific responses to the Brat tumor suppressor and the dMyc proto-oncogene in Drosophila.
abstract: TRIM-NHL proteins are a family of translational regulators that control cell growth, proliferation, and differentiation during development. Drosophila Brat and Mei-P26 TRIM-NHL proteins serve as tumor suppressors in stem cell lineages and have been proposed to exert this action, in part, via the repression of the protooncogene dMyc. Here we analyze the role of Brat, Mei-P26, and dMyc in regulating growth in Drosophila imaginal discs. As in stem cell lineages, Brat and Mei-P26 repress dMyc in epithelial cells by acting at the post-transcriptional and protein level, respectively. Analysis of cell and organ size unravel that Mei-P26 mediates tissue-specific responses to Brat and dMyc activities. Loss-of-function of brat and overexpression of dMyc induce overgrowth in stem cell lineages and eventually can participate in tumor formation. In contrast, an increase in Mei-P26 levels inhibits growth of epithelial cells in these two conditions. Upon depletion of Brat, Mei-P26 up-regulation prevents an increase in dMyc protein levels and leads to tissue undergrowth. This mechanism appears to be tissue-specific since Mei-P26 is not upregulated in brain tumors resulting from brat loss-of-function. Driving Mei-P26 expression in these tumors -mimicking the situation in epithelial cells- is sufficient to prevent dMyc accumulation, thus rescuing the overgrowth. Finally, we show that Mei-P26 upregulation mediates dMyc-induced apoptosis and limits dMyc growth potential in epithelial cells. These findings shed light on the tumor suppressor roles of TRIM-NHL proteins and underscore a new mechanism that maintains tissue homeostasis upon dMyc deregulation.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Ferreira
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Boulan
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain.
authors.forename: Lidia
authors.initials: L
authors.lastname: Perez
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain marco.milan@irbbarcelona.org.
authors.forename: Marco
authors.initials: M
authors.lastname: Milán
mesh_terms: D000818:Animals; D017209:Apoptosis; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004330:Drosophila / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology; D060227:Imaginal Discs / Q000378:metabolism; D009928:Organ Specificity; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C530643:Mei-P26 protein, Drosophila; D016271:Proto-Oncogene Proteins c-myc; C412783:brat protein, Drosophila
keywords: Drosophila; growth; imaginal discs