Δ133p53 coordinates ECM-driven morphogenesis and gene expression in three-dimensional mammary epithelial acini

Sun-Young Lee (Lead / Corresponding author), Claire Robertson, Alexandra Diot, Valerie Meuray, Jean-Christophe Bourdon, Mina J. Bissell (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

Abstract

Growing evidence indicates that p53 (encoded by TP53) has a crucial role in normal tissue development. The role of the canonical p53 (p53α) and its 12 isoforms in development and homeostasis of healthy tissue remains poorly understood. Here, we demonstrate that the Δ133p53 isoforms, the three short isoforms of p53, respond specifically to laminin-111 and play an important regulatory role in formation of mammary organoids in concert with p53α. We demonstrate that down-modulation of Δ133p53 isoforms leads to changes in gene expression of the extracellular matrix molecules fibronectin (FN), EDA+-FN, laminin α5 and laminin α3 in human breast epithelial cells. These changes resulted in increased actin stress fibers and enhanced migratory behavior of cells in two-dimensional culture. We found that α5β1-integrin coupled with the extracellularly deposited EDA+-FN activates the Akt signaling pathway in three-dimensional (3D) culture when Δ133p53 is dysregulated. Cells that do not express detectable Δ133p53 isoforms or express low levels of these isoforms failed to form polarized structures in 3D. These results uncover that Δ133p53 isoforms coordinate expression and deposition of organ-specific ECM molecules that are critical for maintenance of tissue architecture and function.

Original languageEnglish
Article numberjcs259673
Number of pages16
JournalJournal of Cell Science
Volume135
Issue number21
Early online date14 Oct 2022
DOIs
Publication statusPublished - Nov 2022

Keywords

  • Δ133p53
  • ECM
  • Fibronectin
  • Laminin
  • Mammary epithelial cells
  • p53
  • 3D culture
  • Tissue polarity
  • Tissue architecture

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