IRES-mediated functional coupling of transcription and translation amplifies insulin receptor feedback.
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.
Marr
Michael T
MT
Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA.
D'Alessio
Joseph A
JA
Puig
Oscar
O
Tjian
Robert
R
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
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