The LIN28B–IMP1 post-transcriptional regulon has opposing effects on oncogenic signaling in the intestine
- Priya Chatterji1,2,14,
- Kathryn E. Hamilton1,3,14,
- Shun Liang4,
- Sarah F. Andres1,
- H.R. Sagara Wijeratne4,
- Rei Mizuno1,
- Lauren A. Simon1,3,
- Philip D. Hicks1,
- Shawn W. Foley5,
- Jason R. Pitarresi1,
- Andres J. Klein-Szanto6,7,
- Amanda T. Mah8,
- Laurianne Van Landeghem9,
- Brian D. Gregory5,
- Christopher J. Lengner10,
- Blair B. Madison11,
- Premal Shah4,12 and
- Anil K. Rustgi1,2,13
- 1Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19014, USA;
- 2Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19014, USA;
- 3Department of Pediatrics, Division of Gastroenterology, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19014, USA;
- 4Department of Genetics, Rutgers University, New Brunswick, New Jersey 08901, USA;
- 5Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19014, USA;
- 6Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA;
- 7Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA;
- 8Department of Medicine, Hematology Division, Stanford University, Stanford, California 94305, USA;
- 9Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27607, USA;
- 10Department of Biomedical Sciences, School of Veterinary Medicine, Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 11Department of Medicine, Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
- 12Human Genetics Institute of New Jersey, Piscataway, New Jersey 08854 USA;
- 13Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19014, USA
- Corresponding author: anil2{at}pennmedicine.upenn.edu
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↵14 These authors contributed equally to this work.
Abstract
RNA-binding proteins (RBPs) are expressed broadly during both development and malignant transformation, yet their mechanistic roles in epithelial homeostasis or as drivers of tumor initiation and progression are incompletely understood. Here we describe a novel interplay between RBPs LIN28B and IMP1 in intestinal epithelial cells. Ribosome profiling and RNA sequencing identified IMP1 as a principle node for gene expression regulation downstream from LIN28B. In vitro and in vivo data demonstrate that epithelial IMP1 loss increases expression of WNT target genes and enhances LIN28B-mediated intestinal tumorigenesis, which was reversed when we overexpressed IMP1 independently in vivo. Furthermore, IMP1 loss in wild-type or LIN28B-overexpressing mice enhances the regenerative response to irradiation. Together, our data provide new evidence for the opposing effects of the LIN28B–IMP1 axis on post-transcriptional regulation of canonical WNT signaling, with implications in intestinal homeostasis, regeneration and tumorigenesis.
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Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.314369.118.
- Received March 15, 2018.
- Accepted June 4, 2018.
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