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1.
J Cell Sci ; 135(21)2022 11 01.
Article in English | MEDLINE | ID: mdl-36239052

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 α5ß1-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.


Subject(s)
Extracellular Matrix , Tumor Suppressor Protein p53 , Humans , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Extracellular Matrix/genetics , Extracellular Matrix/metabolism , Morphogenesis/genetics , Protein Isoforms/genetics , Protein Isoforms/metabolism , Gene Expression
2.
Elife ; 52016 09 15.
Article in English | MEDLINE | ID: mdl-27630122

ABSTRACT

TP53 is conventionally thought to prevent cancer formation and progression to metastasis, while mutant TP53 has transforming activities. However, in the clinic, TP53 mutation status does not accurately predict cancer progression. Here we report, based on clinical analysis corroborated with experimental data, that the p53 isoform Δ133p53ß promotes cancer cell invasion, regardless of TP53 mutation status. Δ133p53ß increases risk of cancer recurrence and death in breast cancer patients. Furthermore Δ133p53ß is critical to define invasiveness in a panel of breast and colon cell lines, expressing WT or mutant TP53. Endogenous mutant Δ133p53ß depletion prevents invasiveness without affecting mutant full-length p53 protein expression. Mechanistically WT and mutant Δ133p53ß induces EMT. Our findings provide explanations to 2 long-lasting and important clinical conundrums: how WT TP53 can promote cancer cell invasion and reciprocally why mutant TP53 gene does not systematically induce cancer progression.


Subject(s)
Breast Neoplasms/genetics , Colonic Neoplasms/genetics , Neoplasm Recurrence, Local/genetics , Tumor Suppressor Protein p53/genetics , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Movement/genetics , Colonic Neoplasms/pathology , Female , Gene Expression Regulation, Neoplastic , Humans , Mutation , Neoplasm Invasiveness/genetics , Neoplasm Recurrence, Local/pathology , Protein Isoforms/genetics , Tumor Suppressor Protein p53/biosynthesis
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