The LIN28B-IMP1 post-transcriptional regulon has opposing effects on oncogenic signaling in the intestine

Genes Dev. 2018 Aug 1;32(15-16):1020-1034. doi: 10.1101/gad.314369.118.

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.

Keywords: IMP1; LIN28B; intestinal tumorigenesis; post-transcriptional regulation; ribosome profiling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis*
  • Cell Line, Tumor
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Gene Expression Regulation*
  • Humans
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / physiology
  • Mice
  • Mice, Transgenic
  • Oncogenes
  • Protein Biosynthesis
  • RNA-Binding Proteins / metabolism*
  • RNA-Binding Proteins / physiology
  • Regeneration
  • Regulon*
  • Stem Cells / metabolism
  • Wnt Signaling Pathway*

Substances

  • IGF2BP1 protein, human
  • IMP1 protein, mouse
  • LIN28B protein, human
  • RNA-Binding Proteins