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

Area of Science:

• Cell Biology
• Developmental Biology
• Molecular Biology

Background:

• The tumor suppressor p53 (encoded by TP53) is vital for normal tissue development.
• The specific roles of canonical p53 (p53α) and its 12 isoforms in tissue homeostasis are not fully understood.

Purpose of the Study:

• To investigate the role of Δ133p53 isoforms in mammary organoid formation and tissue development.
• To elucidate the regulatory mechanisms involving Δ133p53 isoforms, extracellular matrix (ECM) molecules, and cell behavior.

Main Methods:

• Studied the response of Δ133p53 isoforms to laminin-111 in human breast epithelial cells.
• Analyzed gene expression changes of ECM molecules (fibronectin, laminin) upon Δ133p53 down-modulation.
• Investigated cell migration and actin stress fiber formation in 2D culture.
• Examined Akt signaling pathway activation and cell polarization in 3D culture.

Main Results:

• Δ133p53 isoforms regulate mammary organoid formation with p53α.
• Down-modulation of Δ133p53 alters ECM gene expression (FN, EDA+-FN, laminin α5, α3), increasing cell migration.
• Dysregulated Δ133p53 and EDA+-FN activate Akt signaling via α5β1-integrin in 3D culture.
• Low or absent Δ133p53 isoforms result in failure to form polarized 3D structures.

Conclusions:

• Δ133p53 isoforms are crucial regulators of mammary organoid development.
• These isoforms coordinate the expression and deposition of specific ECM molecules essential for tissue architecture and function.
• Understanding Δ133p53's role provides insights into maintaining healthy tissue homeostasis.