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Mutational inactivation of Apc in the intestinal epithelia compromises cellular organisation.

Authors
  • Rannikmae, Helena1
  • Peel, Samantha2
  • Barry, Simon3
  • Senda, Takao4
  • de la Roche, Marc5
  • 1 Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK.
  • 2 Discovery Science, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB4 0WG, UK.
  • 3 Bioscience, Oncology R&D, AstraZeneca, Cambridge CB2 0RE, UK.
  • 4 Department of Anatomy, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan. , (Japan)
  • 5 Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK [email protected]
Type
Published Article
Journal
Journal of Cell Science
Publisher
The Company of Biologists
Publication Date
Jan 27, 2021
Volume
134
Issue
2
Identifiers
DOI: 10.1242/jcs.250019
PMID: 33335067
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The adenomatous polyposis coli (Apc) protein regulates diverse effector pathways essential for tissue homeostasis. Truncating oncogenic mutations in Apc removing its Wnt pathway and microtubule regulatory domains drives intestinal epithelia tumorigenesis. Exuberant cell proliferation is one well-established consequence of oncogenic Wnt pathway activity; however, the contribution of other deregulated molecular circuits to tumorigenesis has not been fully examined. Using in vivo and organoid models of intestinal epithelial tumorigenesis we found that Wnt pathway activity controls intestinal epithelial villi and crypt structure, morphological features lost upon Apc inactivation. Although the Wnt pathway target gene c-Myc (also known as Myc) has critical roles in regulating cell proliferation and tumorigenesis, Apc specification of intestinal epithelial morphology is independent of the Wnt-responsive Myc-335 (also known as Rr21) regulatory element. We further demonstrate that Apc inactivation disrupts the microtubule cytoskeleton and consequently localisation of organelles without affecting the distribution of the actin cytoskeleton and associated components. Our data indicates the direct control over microtubule dynamics by Apc through an independent molecular circuit. Our study stratifies three independent Apc effector pathways in the intestinal epithelial controlling: (1) proliferation, (2) microtubule dynamics and (3) epithelial morphology.This article has an associated First Person interview with the first author of the paper. © 2021. Published by The Company of Biologists Ltd.

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