title: IRES-mediated functional coupling of transcription and translation amplifies insulin receptor feedback.
abstract: It is generally accepted that the growth rate of an organism is modulated by the availability of nutrients. One common mechanism to control cellular growth is through the global down-regulation of cap-dependent translation by eIF4E-binding proteins (4E-BPs). Here, we report evidence for a novel mechanism that allows eukaryotes to coordinate and selectively couple transcription and translation of target genes in response to a nutrient and growth signaling cascade. The Drosophila insulin-like receptor (dINR) pathway incorporates 4E-BP resistant cellular internal ribosome entry site (IRES) containing mRNAs, to functionally couple transcriptional activation with differential translational control in a cell that is otherwise translationally repressed by 4E-BP. Although examples of cellular IRESs have been previously reported, their critical role mediating a key physiological response has not been well documented. Our studies reveal an integrated transcriptional and translational response mechanism specifically dependent on a cellular IRES that coordinates an essential physiological signal responsible for monitoring nutrient and cell growth conditions.
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Marr
authors.forename: Joseph A
authors.initials: JA
authors.lastname: D'Alessio
authors.forename: Oscar
authors.initials: O
authors.lastname: Puig
authors.forename: Robert
authors.initials: R
authors.lastname: Tjian
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D025461:Feedback, Physiological; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D007328:Insulin / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011972:Receptor, Insulin / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D020121:5' Untranslated Regions; D029721:Drosophila Proteins; D039561:Eukaryotic Initiation Factor-4E; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D007328:Insulin; C105238:cup protein, Drosophila; D011972:Receptor, Insulin