The ability to suppress wild type p53-independent apoptosis may play an important role in the oncogenicity of p53 mutant proteins. However, structural elements necessary for this activity are unknown. Furthermore, it is unclear whether this mutant p53 mediated inhibition is specific to the apoptotic pathway or a more general suppression of the cellular response to stress. We observed that an unmodified C-terminus was required for the suppression of apoptosis by the p53 135(Ala to Val) oncogenic p53 mutant. It was also required for the novel activity of G2 arrest suppression, the predominant response at low levels of genotoxic stress. These observations are consistent with a model whereby mutant p53 suppressive activity is not specific to the apoptotic pathway, but rather increases the threshold of genotoxic stress needed for a DNA damage response to occur. Furthermore, these observations indicate that it may be possible to selectively kill mutant p53 expressing cells based on the lower sensitivity of their growth arrest response.
Bibliographical noteFunding Information:
A Sigal wishes to thank Ayala Sharp and Eitan Ariel for lessons in flow cytometry. This work was supported in part by grants from the Israel-USA Binational Science Foundation (BSF) the DIP (Deutsch-Israelische Projektkoopera-tion) and the Kadoori Foundation. V Rotter is the incumbent of the Norman and Helen Asher Professorial Chair in Cancer Research at the Weizmann Institute.
- Gain of function
- Growth arrest
- Mutant p53