Abstract
BackgroundNutrient availability is a key determinant of eukaryotic cell growth. In unicellular organisms many signaling and transcriptional networks link nutrient availability to the expression of metabolic genes required for growth. However, less is known about the corresponding mechanisms that operate in metazoans. We used gene expression profiling to explore this issue in developing Drosophila larvae.ResultsWe found that starvation for dietary amino acids (AA's) leads to dynamic changes in transcript levels of many metabolic genes. The conserved insulin/PI3K and TOR signaling pathways mediate nutrition-dependent growth in Drosophila and other animals. We found that many AA starvation-responsive transcripts were also altered in TOR mutants. In contrast, although PI3K overexpression induced robust changes in the expression of many metabolic genes, these changes showed limited overlap with the AA starvation expression profile. We did however identify a strong overlap between genes regulated by the transcription factor, Myc, and AA starvation-responsive genes, particularly those involved in ribosome biogenesis, protein synthesis and mitochondrial function. The consensus Myc DNA binding site is enriched in promoters of these AA starvation genes, and we found that Myc overexpression could bypass dietary AA to induce expression of these genes. We also identified another sequence motif (Motif 1) enriched in the promoters of AA starvation-responsive genes. We showed that Motif 1 was both necessary and sufficient to mediate transcriptional responses to dietary AA in larvae.ConclusionsOur data suggest that many of the transcriptional effects of amino acids are mediated via signaling through the TOR pathway in Drosophila larvae. We also find that these transcriptional effects are mediated through at least two mechanisms: via the transcription factor Myc, and via the Motif 1 cis-regulatory element. These studies begin to elucidate a nutrient-responsive signaling network that controls metabolic gene transcription in Drosophila.
Highlights
Nutrient availability is a key determinant of eukaryotic cell growth
Of the transcripts with GO term annotations, approximately one-third were involved in ribosome biogenesis and protein synthesis while another one-third of reduced transcripts were annotated as being involved in nutrient metabolism, including many genes required for mitochondrial function (Figure B and Additional File 3)
amino acids (AAs) starvation leads to a block in cell cycle progression in most larval tissues, the endoreplicating tissues which make up the bulk of the animal, transcripts coding for cell cycle genes were largely unaffected by starvation (Additional File 6)
Summary
Nutrient availability is a key determinant of eukaryotic cell growth. In unicellular organisms many signaling and transcriptional networks link nutrient availability to the expression of metabolic genes required for growth. In single cell organisms, such as budding yeast, an extensive signal transduction and transcriptional network links extracellular nutrients to the expression of metabolic genes [1,2]. These networks are essential for the proper control of cell growth and proliferation [3,4]. In response to dietary protein, Drosophila insulin-like peptides (Dilps) are released from neurosecretory cells These Dilps act in an endocrine manner and trigger growth by binding to the insulin receptor and activating a conserved PI3 kinase (PI3K) and Akt kinase signaling pathway in all larval tissues [7].
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