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Bax suppresses tumorigenesis and stimulates apoptosis in vivo
C Yin1, C M Knudson, S J Korsmeyer
1Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine at Chapel Hill, 27599, USA.
Abstract:
The protein p53 is a key tumour-suppressor, as evidenced by its frequent inactivation in human cancers. Animal models have indicated that attenuation of p53-dependent cell death (apoptosis) can contribute to both the initiation and progression of cancer, but the molecular mechanisms are unknown. Although p53-mediated transcriptional activation is one possible explanation, none of the known p53-responsive genes has been shown to function in p53-dependent apoptosis. Here we test the role of the death-promoting gene bax in a transgenic mouse brain tumour, a model in which p53-mediated apoptosis attenuates tumour growth. Inactivation of p53 causes a dramatic acceleration of tumour growth owing to a reduction in apoptosis of over ninety per cent. We show that p53-dependent expression of bax is induced in slow-growing apoptotic tumours. Moreover, tumour growth is accelerated and apoptosis drops by fifty per cent in Bax-deficient mice, indicating that it is required for a full p53-mediated response. To our knowledge this is the first demonstration that Bax acts as a tumour suppressor, and our findings indicate that Bax could be a component of the p53-mediated apoptotic response in this system.
Insights
The tumor suppressor protein p53 normally induces apoptosis via the BAX gene to slow tumor growth. Loss of p53 or BAX function accelerates brain tumor development in mice, highlighting BAX
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- The protein p53 is a crucial tumor suppressor frequently inactivated in human cancers.
- Attenuation of p53-dependent apoptosis contributes to cancer initiation and progression, but mechanisms remain unclear.
- p53-mediated transcriptional activation is a potential mechanism, yet no direct p53-responsive apoptosis genes are identified.
Purpose of the Study:
- To investigate the role of the pro-apoptotic gene BAX in p53-mediated apoptosis within a mouse brain tumor model.
- To determine if BAX acts as a tumor suppressor in the context of p53 inactivation.
- To elucidate the molecular mechanisms linking p53, apoptosis, and tumor suppression.
Main Methods:
- Utilized a transgenic mouse brain tumor model to study p53-mediated apoptosis.
- Assessed the impact of p53 inactivation on tumor growth and apoptosis rates.
- Examined BAX gene expression in relation to tumor growth and apoptosis.
- Generated and analyzed Bax-deficient mice to evaluate BAX's requirement in p53-mediated tumor suppression.
Main Results:
- Inactivation of p53 dramatically accelerated brain tumor growth, reducing apoptosis by over 90%.
- p53-dependent BAX expression was induced in slow-growing, apoptotic tumors.
- Bax-deficient mice exhibited accelerated tumor growth and a 50% reduction in apoptosis, confirming BAX's role.
Conclusions:
- BAX is demonstrated as a tumor suppressor, acting as a key component of the p53-mediated apoptotic response in this brain tumor model.
- These findings provide the first evidence of BAX functioning as a tumor suppressor.
- The study elucidates a critical molecular link between p53, BAX, and apoptosis in controlling tumor progression.