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p63 promotes cell survival through fatty acid synthase
Venkata Sabbisetti1, Arianna Di Napoli, Apryle Seeley
1Department of Pathology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Plos One
|June 12, 2009
Summary
The transcription factor p63 promotes epithelial cell survival by regulating Fatty Acid Synthase (FASN). FASN is crucial for p63
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- p63, particularly DeltaNp63, is vital for epithelial cell survival during development and in cancer.
- The precise molecular mechanisms underlying p63's pro-survival role are not fully understood.
- Fatty acid synthase (FASN) is implicated in embryogenesis and cancer and is a potential target of p53 family members.
Purpose of the Study:
- To investigate the molecular mechanisms by which p63 promotes epithelial cell survival.
- To determine if FASN is a direct target of p63 and mediates its pro-survival functions.
Main Methods:
- Knockdown of p63 isoforms in squamous cell carcinoma (SCC9) and immortalized prostate epithelial (iPrEC) cells.
- Assessment of cell viability, apoptosis, and cell cycle.
- Measurement of FASN expression and activity.
- Overexpression of FASN or myristoylated AKT (myr-AKT) to assess rescue effects.
- Analysis of AKT phosphorylation and inhibition.
- Correlation of p63 and FASN expression in clinical samples.
Main Results:
- p63 knockdown reduced cell viability by inducing apoptosis without affecting the cell cycle.
- Silencing p63 decreased both FASN expression and activity.
- Overexpression of FASN or myr-AKT partially rescued cells from p63-silencing-induced death.
- FASN induced AKT phosphorylation, and AKT inhibition further reduced viability in FASN-overexpressing cells after p63 knockdown.
- Activated AKT enhanced FASN activity, suggesting a role in FASN-mediated survival.
- p63 and FASN expression were positively associated in clinical squamous cell carcinoma and developing prostate tissues.
Conclusions:
- Fatty acid synthase (FASN) is a functionally relevant target of p63.
- FASN mediates the pro-survival effects of p63 in epithelial cells.
- The p63-FASN-AKT signaling axis is important for epithelial cell survival and potentially tumorigenesis.
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