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The c-fos proto-oncogene is a target for transactivation by the p53 tumor suppressor
A Elkeles1, T Juven-Gershon, D Israeli
1Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Abstract:
The p53 tumor suppressor gene is mutated in over 50% of human cancers, resulting in inactivation of the wild-type (wt) p53 protein. The most notable biochemical feature of p53 is its ability to act as a sequence-specific transcriptional activator. Through use of the suppression subtractive hybridization differential screening technique, we identified c-fos as a target for transcriptional stimulation by p53 in cells undergoing p53-mediated apoptosis. Overexpression of wt p53 induces c-fos mRNA and protein. Moreover, in vivo induction of c-fos in the thymus following whole-body exposure to ionizing radiation is p53 dependent. p53 responsiveness does not reside in the basal c-fos promoter. Rather, a distinct region within the c-fos gene first intron binds specifically to p53 and confers upon the c-fos promoter the ability to become transcriptionally activated by wt p53. Identification of c-fos as a specific target for transcriptional activation by p53 establishes a direct link between these two pivotal regulatory proteins and raises the possibility that c-fos contributes to some of the biological effects of p53.
Insights
The p53 tumor suppressor gene, crucial in preventing cancer, activates the c-fos gene during apoptosis. This p53-dependent c-fos induction links these key regulatory proteins, potentially influencing p53
Area of Science:
- Molecular Biology
- Cancer Research
- Gene Regulation
Background:
- The p53 tumor suppressor gene is frequently inactivated in human cancers.
- Wild-type (wt) p53 functions as a sequence-specific transcriptional activator.
- Understanding p53's transcriptional targets is key to cancer biology.
Purpose of the Study:
- To identify genes transcriptionally activated by p53.
- To investigate the relationship between p53 and c-fos expression.
- To elucidate the mechanism of p53-mediated c-fos induction.
Main Methods:
- Suppression subtractive hybridization differential screening.
- Analysis of c-fos mRNA and protein levels.
- In vivo studies of thymic c-fos induction post-irradiation.
Main Results:
- c-fos was identified as a direct transcriptional target of p53.
- Overexpression of wt p53 induced c-fos mRNA and protein.
- Ionizing radiation-induced c-fos in vivo was p53-dependent.
- A specific region in the c-fos first intron, not the basal promoter, mediates p53 binding and activation.
Conclusions:
- A direct link between p53 and c-fos has been established.
- The c-fos gene's first intron contains a p53-responsive element.
- c-fos may contribute to the biological functions of p53 in apoptosis and tumor suppression.