Related Experiment Videos
Cell surface trafficking of Fas: a rapid mechanism of p53-mediated apoptosis
M Bennett1, K Macdonald, S W Chan
1Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK.
Abstract:
p53 acts as a tumor suppressor by inducing both growth arrest and apoptosis. p53-induced apoptosis can occur without new RNA synthesis through an unknown mechanism. In human vascular smooth muscle cells, p53 activation transiently increased surface Fas (CD95) expression by transport from the Golgi complex. Golgi disruption blocked both p53-induced surface Fas expression and apoptosis. p53 also induced Fas-FADD binding and transiently sensitized cells to Fas-induced apoptosis. In contrast, lpr and gld fibroblasts were resistant to p53-induced apoptosis. Thus, p53 can mediate apoptosis through Fas transport from cytoplasmic stores.
Insights
The tumor suppressor p53 protein triggers apoptosis, programmed cell death, partly by moving the Fas receptor to the cell surface. This mechanism bypasses the need for new RNA synthesis.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- The p53 protein is a critical tumor suppressor.
- p53 induces growth arrest and apoptosis to prevent cancer.
- The mechanism of p53-induced apoptosis, particularly when independent of new RNA synthesis, remains incompletely understood.
Purpose of the Study:
- To elucidate the mechanism of p53-induced apoptosis in human vascular smooth muscle cells.
- To investigate the role of Fas (CD95) receptor trafficking in p53-mediated apoptosis.
- To determine if p53-induced apoptosis occurs via a novel RNA-independent pathway involving Fas.
Main Methods:
- Human vascular smooth muscle cells were treated to activate p53.
- Surface expression of Fas (CD95) was measured following p53 activation.
- Golgi complex integrity was disrupted using specific inhibitors.
- Fas-FADD binding assays were performed.
- Apoptosis assays were conducted in wild-type and Fas-deficient (lpr/gld) fibroblasts.
Main Results:
- p53 activation led to a transient increase in surface Fas expression, originating from the Golgi complex.
- Disruption of the Golgi apparatus abrogated both p53-induced surface Fas expression and apoptosis.
- p53 activation promoted Fas-FADD binding, sensitizing cells to Fas-mediated apoptosis.
- Fibroblasts with mutations in Fas (lpr/gld) were resistant to p53-induced apoptosis.
Conclusions:
- p53 can induce apoptosis through a mechanism involving the transport of the Fas receptor from cytoplasmic stores (Golgi) to the cell surface.
- This pathway allows for RNA-independent apoptosis induction by p53.
- The findings reveal a novel route for p53-mediated programmed cell death involving receptor trafficking.