RBP-L and RBP-J Have Critical Roles in the Functioning of Two Forms of the Pancreas Transcription Factor Complex PTF1

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2005-05-04

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Beres, Thomas Matthew

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The decision of pancreatic precursor cells to differentiate into acinar or endocrine cells is regulated by a complex network of signaling and transcription factor pathways. P48 is a tissue-specific basic-helix-loop-helix (bHLH) transcription factor, which is essential for pancreas development and function. Mice lacking both p48 alleles lack an exocrine pancreas and have a greatly reduced endocrine pancreas. The active form of P48 is the heterotrimeric complex, PTF1. This complex binds and regulates the transcription of genes encoding digestive enzymes within the exocrine pancreas. The PTF1 complex forms on the rat elastase 1 (ELA1) promoter by synergistically binding to a 21 base-pair site comprising an E-box (CANNTG) and a TC-box separated by one helical turn. P48 binds the E-box as a heterodimer with class A bHLH proteins, while the third member of the complex contacts the TC-box, but cannot stably bind without the P48 heterodimer. PTF1 activates the genes encoding the digestive enzymes specifically in the acinar cells of the pancreas, but no developmentally relevent target genes for P48 have been identified. Human mutations that truncate P48 are associated with permanent neonatal diabetes mellitus (PNDM), a genetic disorder characterized by pancreatic and cerebellar agenesis. DNA binding and transcriptional activity of PTF1 is dependent on the interaction of P48 with either RBP-J, or its paralogue, RBP-L. The exclusive form of PTF1 in mature pancreatic acinar cells is a potent transcriptional activator containing RBP-L; however, RBP-J can form a similar, but low activity, complex. The P48-RBP interaction is primarily through two conserved peptides that resemble the RBP-J-interacting motif of the Notch intracellular domain (NotchIC). However, the NotchIC is excluded from PTF1 because it lacks affinity for RBP-L, and P48 occupies its docking site on RBP-J. PNDM associated mutations delete one or both critical peptides, indicating the requirement of a PTF1 complex for proper embryonic development. The inability of the NotchIC to integrate into PTF1 complexes demonstrates a Notch-independent role for mammalian Suppressor of Hairless (RBP-J) and its paralogue RBP-L.

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