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bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis
M E McCurrach1, T M Connor, C M Knudson
1Cold Spring Harbor Laboratory, New York 11724, USA.
Abstract:
Inactivation of p53-dependent apoptosis promotes oncogenic transformation, tumor development, and resistance to many cytotoxic anticancer agents. p53 can transcriptionally activate bax, a bcl-2 family member that promotes apoptosis. To determine whether bax is required for p53-dependent apoptosis, the effects of bax deficiency were examined in primary fibroblasts expressing the E1A oncogene, a setting where apoptosis is dependent on endogenous p53. We demonstrate that bax can function as an effector of p53 in chemotherapy-induced apoptosis and contributes to a p53 pathway to suppress oncogenic transformation. Furthermore, we show that additional p53 effectors participate in these processes. These p53-controlled factors act synergistically with Bax to promote a full apoptotic response, and their action is suppressed by the Bcl-2 and E1B 19K oncoproteins. These studies demonstrate that Bax is a determinant of p53-dependent chemosensitivity and illustrate how p53 can promote apoptosis by coordinating the activities of multiple effectors.
Insights
The tumor suppressor p53 protein induces apoptosis via the BAX gene, crucial for suppressing cancer development and enhancing chemotherapy sensitivity. Bax acts as a key effector, working with other factors to eliminate cancer cells.
Area of Science:
- Molecular Biology
- Cancer Biology
- Cell Death Research
Background:
- The tumor suppressor protein p53 plays a critical role in preventing oncogenic transformation and tumor development.
- p53 induces apoptosis, a key mechanism for eliminating damaged or cancerous cells, and its inactivation leads to resistance against cancer therapies.
- The BAX gene, a member of the BCL-2 family, is known to promote apoptosis and is transcriptionally regulated by p53.
Purpose of the Study:
- To investigate whether BAX is essential for p53-mediated apoptosis.
- To elucidate the role of BAX as an effector in p53-dependent apoptosis, particularly in the context of chemotherapy.
- To identify other p53-regulated factors that contribute to apoptosis and oncogenic suppression.
Main Methods:
- Utilized primary fibroblasts engineered to express the E1A oncogene, a system where endogenous p53 controls apoptosis.
- Examined the effects of BAX deficiency on apoptosis induction in response to chemotherapy.
- Investigated the interplay between BAX, other p53 effectors, and apoptosis-suppressing oncoproteins like Bcl-2 and E1B 19K.
Main Results:
- Demonstrated that BAX functions as a critical effector of p53 in chemotherapy-induced apoptosis.
- Confirmed that BAX contributes to the p53 pathway that suppresses oncogenic transformation.
- Identified additional p53-controlled factors that act synergistically with BAX to achieve a full apoptotic response.
- Showed that the apoptotic activity of these factors is inhibited by Bcl-2 and E1B 19K oncoproteins.
Conclusions:
- BAX is a key determinant of p53-dependent chemosensitivity.
- p53 promotes apoptosis by coordinating the activities of multiple effector proteins, including BAX.
- Understanding this p53-effector network provides insights into cancer development and therapeutic resistance.