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Bcl-XL protects cancer cells from p53-mediated apoptosis
A F Schott1, I J Apel, G Nuñez
1Department of Hematology-Oncology, University of Michigan, Ann Arbor 48109, USA.
Abstract:
Oncogenesis is a process resulting from genetic events which cause loss of growth control or inhibition of appropriate cell death. The Bcl-XL protein is a recently discovered member of the bcl-2 family which has been shown to protect cells from some forms of programmed cell death, but has not yet been implicated in the genesis of human carcinomas. In this report we explore the role of Bcl-XL overexpression in protecting cancer cells from p53-mediated apoptosis. Increased levels of Bcl-XL were found in a subset of primary human breast carcinomas, as well as in the breast cancer line, T47D. T47D cells were then transfected with a temperature-sensitive mutant of the tumor suppressor p53 (p53ts). Although many tumor cell lines undergo apoptosis when p53 is expressed, the T47D transfectants remained viable at temperatures permitting wild-type p53 phenotype. This suggested that endogenous Bcl-XL could protect cancer cells from p53-mediated apoptosis. To test this hypothesis, murine erythroleukemia cells were transfected with bcl-XL and p53ts. While cell lines expressing p53 alone rapidly died, those cells co-expressing Bcl-XL survived. These results demonstrate that Bcl-XL is capable of protecting cells from p53-mediated apoptosis, and suggest a possible mechanism by which tumors expressing Bcl-XL are able to partly overcome the tumor suppressor functions of p53.
Insights
Bcl-XL protein overexpression protects cancer cells from p53-mediated apoptosis. This suggests Bcl-XL may help tumors evade the tumor suppressor functions of p53, contributing to oncogenesis.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Death Mechanisms
Background:
- Oncogenesis involves genetic events leading to uncontrolled cell growth or inhibited cell death.
- Bcl-XL, a bcl-2 family protein, protects cells from programmed cell death.
- Bcl-XL's role in human carcinoma genesis, particularly in relation to p53, was previously unclear.
Purpose of the Study:
- To investigate the role of Bcl-XL overexpression in protecting cancer cells from p53-mediated apoptosis.
- To determine if Bcl-XL can counteract the tumor suppressor functions of p53.
Main Methods:
- Assessed Bcl-XL levels in human breast carcinomas and breast cancer cell lines.
- Transfected T47D breast cancer cells with a temperature-sensitive mutant of p53 (p53ts).
- Co-expressed Bcl-XL and p53ts in murine erythroleukemia cells to assess cell survival.
Main Results:
- Elevated Bcl-XL levels were observed in a subset of primary human breast carcinomas and the T47D cell line.
- T47D cells expressing p53ts survived, indicating endogenous Bcl-XL protected them from p53-induced apoptosis.
- Murine cells co-expressing Bcl-XL and p53ts survived, while those with p53 alone underwent apoptosis.
Conclusions:
- Bcl-XL actively protects cells from p53-mediated apoptosis.
- Overexpression of Bcl-XL may enable tumors to partially overcome the suppressive effects of p53.
- This provides a potential mechanism for tumor development and progression in certain carcinomas.