LAUSR

Significance Here, we explore a mechanism wherein the growth signaling-dependent translation of mRNA encoding a cell cycle regulatory factor limits rates of cell proliferation. An essential cell cycle transcription factor, E2F1, was found to be post-transcriptionally regulated by TOR and EGFR signaling, and thus served as a candidate growth sensor for this study. Using expression of green fluorescent protein (GFP)-E2F1 transgenes with alterations within the E2f1 5′ untranslated region (UTR), we altered the translation of GFP-E2F1 and changed cell proliferation rates accordingly. Further, we found that 5′UTR upstream open reading frames are TOR-sensitive regulatory components of E2f1 translation. Our observations indicate that growth signaling dependent protein translation is an important regulator of cell proliferation. E2F transcription factors are master regulators of the eukaryotic cell cycle. In Drosophila, the sole activating E2F, E2F1, is both required for and sufficient to promote G1→S progression. E2F1 activity is regulated both by binding to RB Family repressors and by posttranscriptional control of E2F1 protein levels by the EGFR and TOR signaling pathways. Here, we investigate cis-regulatory elements in the E2f1 messenger RNA (mRNA) that enable E2f1 translation to respond to these signals and promote mitotic proliferation of wing imaginal disc and intestinal stem cells. We show that small upstream open reading frames (uORFs) in the 5′ untranslated region (UTR) of the E2f1 mRNA limit its translation, impacting rates of cell proliferation. E2f1 transgenes lacking these 5′UTR uORFs caused TOR-independent expression and excess cell proliferation, suggesting that TOR activity can bypass uORF-mediated translational repression. EGFR signaling also enhanced translation but through a mechanism less dependent on 5′UTR uORFs. Further, we mapped a region in the E2f1 mRNA that contains a translational enhancer, which may also be targeted by TOR signaling. This study reveals translational control mechanisms through which growth signaling regulates cell cycle progression.