Mei-P26 Mediates Tissue-Specific Responses to the Brat Tumor Suppressor and the dMyc Proto-Oncogene inDrosophila

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 tissuespecific 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 lossof-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.

TRIM71 suppresses tumorigenesis via modulation of Lin28B-let-7-HMGA2 signaling

“…As members the TRIM-NHL protein family, TRIM2, TRIM3, TRIM32 and TRIM71 share structural homology in the C-terminus, which contains a filamin domain and NHL-repeat motifs [ 1 , 23 – 26 ]. Moreover, TRIM71 shares functional homology with other TRIM-NHL family proteins in terms of ubiquitin ligase activity.…”

“…In addition, several groups have implicated TRIM32 in tumor formation based on studies initially performed in Drosophila melanogaster [ 1 ]. These early studies showed that mutations in brat and mei-26, ortholog of TRIM32 in the fly, cause tumor formation in Drosophila [ 23 ]. In mammalian cells, TRIM32 has been shown to modulate TNF-mediated apoptosis through ubiquitination of XIAP (X-linked inhibitor of apoptosis) [ 27 ].…”

WD40 protein Wuho controls germline homeostasis via TRIM-NHL tumor suppressor Mei-p26 in Drosophila

“…Interestingly, immunoprecipitation with ovary lysates showed that Wh interacted with dMyc ( Fig. 6K), which is targeted by Mei-p26 for degradation in the wing disc (Ferreira et al, 2014). Removal of one dmyc copy from nos>wh RNAi germaria significantly rescued the number of large nucleoli present in GSCs or early germ cells (Fig.…”

Screening of suppressors of bax-induced cell death identifies glycerophosphate oxidase-1 as a mediator of debcl-induced apoptosis in Drosophila

“…This mutation strongly suppressed (α=7.3×10 −7 ) the wing phenotype showing that UY1131 is a LOF of brat (data not shown). Brat belongs to the NHL family of proteins, represses translation of specific mRNAs 38] and is a negative regulator of cell growth [39-41]. The suppression of bax -induced phenotypes by a LOF of brat could suggest that this gene also regulates cell death, which seems unlikely according to its inability to suppress other cell death pathways [37].…”