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P53 is necessary for the apoptotic response mediated by a transient increase of Ras activity
Peihong Ma1, Maureen Magut, XinBin Chen
1Cancer Research Center and Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Abstract:
The tumor suppressor p53 eliminates cancer-prone cells via multiple mechanisms, including apoptosis. Ras elicits apoptosis in cells after protein kinase C (PKC) downregulation. However, the role of p53 in Ras-mediated apoptosis has not been fully investigated. Here, we demonstrate that mouse fibroblasts that express wild-type p53 are more susceptible to apoptosis elicited by PKC inhibition if Ras is transiently expressed or upregulated as opposed to stably expressed. In the latter case, p53 is frequently mutated. Transiently increased Ras activity induces Bax, and PKC inhibition augments this induction. Overexpression of E6 inactivates p53 and thereby suppresses both Bax induction and apoptosis. In contrast, Bax is not induced in stable ras transfectants, regardless of PKC inhibition. The data suggest that short- and long-term activation of Ras use a different mechanism(s) to initiate apoptosis. The status of p53 may contribute to such differences.
Insights
The tumor suppressor p53 promotes apoptosis when Ras is transiently activated and protein kinase C (PKC) is inhibited. However, mutated p53 in cells with stable Ras activation prevents this apoptotic response, highlighting p53
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- The tumor suppressor p53 induces apoptosis in pre-cancerous cells.
- Ras signaling can trigger apoptosis following protein kinase C (PKC) downregulation.
- The interplay between p53 and Ras-mediated apoptosis requires further investigation.
Purpose of the Study:
- To investigate the role of p53 in Ras-mediated apoptosis.
- To explore how transient versus stable Ras activation affects apoptosis.
- To understand the influence of p53 status on Ras-induced apoptosis.
Main Methods:
- Utilized mouse fibroblasts expressing wild-type or mutated p53.
- Manipulated Ras expression (transient vs. stable) and PKC activity.
- Assessed apoptosis induction, Bax expression, and p53 functional status (e.g., via E6 inactivation).
Main Results:
- Wild-type p53-expressing cells showed increased apoptosis upon PKC inhibition with transient Ras activation.
- Transient Ras activation, coupled with PKC inhibition, augmented Bax induction.
- Stable Ras expression, often with mutated p53, did not induce Bax or apoptosis, even with PKC inhibition.
- E6-mediated p53 inactivation suppressed Bax induction and apoptosis.
Conclusions:
- Transient and long-term Ras activation employ distinct mechanisms for apoptosis initiation.
- The functional status of p53 is critical in determining the apoptotic outcome of Ras signaling.
- p53's role in apoptosis is context-dependent, influenced by Ras activation dynamics and PKC activity.