The C-terminus of mutant p53 is necessary for its ability to interfere with growth arrest or apoptosis.
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.
Sigal
A
A
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel.
Matas
D
D
Almog
N
N
Goldfinger
N
N
Rotter
V
V
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology; D016195:G2 Phase; D006801:Humans; D051379:Mice; D009154:Mutation; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D002945:Cisplatin