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Repression of p63 and induction of EMT by mutant Ras in mammary epithelial cells.

ABSTRACT: The p53-related transcription factor p63 is required for maintenance of epithelial cell differentiation. We found that activated forms of the Harvey Rat Sarcoma Virus GTPase (H-RAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) oncogenes strongly repress expression of ?Np63?, the predominant p63 isoform in basal mammary epithelial cells. This regulation occurs at the transcriptional level, and a short region of the ?Np63 promoter is sufficient for repression induced by H-RasV12. The suppression of ?Np63? expression by these oncogenes concomitantly leads to an epithelial-to-mesenchymal transition (EMT). In addition, the depletion of ?Np63? alone is sufficient to induce EMT. Both H-RasV12 expression and ?Np63? depletion induce individual cell invasion in a 3D collagen gel in vitro system, thereby demonstrating how Ras can drive the mammary epithelial cell state toward greater invasive ability. Together, these results suggest a pathway by which RAS and PIK3CA oncogenes induce EMT through regulation of ?Np63?.

SUBMITTER: Yoh KE

PROVIDER: S-EPMC5068336 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Repression of p63 and induction of EMT by mutant Ras in mammary epithelial cells.

Yoh Kathryn E KE Regunath Kausik K Guzman Asja A Lee Seung-Min SM Pfister Neil T NT Akanni Olutosin O Kaufman Laura J LJ Prives Carol C Prywes Ron R

Proceedings of the National Academy of Sciences of the United States of America 20160928 41

The p53-related transcription factor p63 is required for maintenance of epithelial cell differentiation. We found that activated forms of the Harvey Rat Sarcoma Virus GTPase (H-RAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) oncogenes strongly repress expression of ∆Np63α, the predominant p63 isoform in basal mammary epithelial cells. This regulation occurs at the transcriptional level, and a short region of the ∆Np63 promoter is sufficient for repression ...[more]

PMID: 27681615

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Repression of p63 and induction of EMT by mutant Ras in mammary epithelial cells.

Publications

Repression of p63 and induction of EMT by mutant Ras in mammary epithelial cells.

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