genes or through the binding to different biological partners,
reshaping the network of p53 protein–protein interactions, and
introducing or silencing post-translational modification sites or a
combination of the mechanisms mentioned above. The emerging
mechanisms by which mutant p53 exhibits its GOF when it comes
to different protein-protein interactions are: (a) the formation of
complexes with other proteins that modify their activities (such as
p63 or p73); (b) the interaction with other transcription factors
(mainly VDR, SREBP, and Est2) that allows regulating promoters
that are generally not under wild-type p53 control; and (c) the
remodeling of chromatin through interactions with chromatinremodeling proteins (such as SWI-SNF CRC and Pontin) or inducing chromatin regulatory gene expression (for example MLL1,
MLL2, and MOZ). These mechanisms are not mutually exclusive
in the onset of different cancers and are also likely to be contextdependent [1].
Mutant p53 proteins have been for a long time expected to be
“undruggable” but recent studies suggest the opposite, as recapitulated in a comprehensive review article [12]. These studies provide important proofs of concept that it is possible to rescue the
structural mutants of p53. However, several efforts are still required
in the direction of cancer therapy and personalized medicine. In
this context, the identification of the complex mechanisms that
trigger mutant p53 GOF activities becomes essential to provide
tailored solutions for new treatments to undermine mutant p53
activities.
It is also essential to understand in detail the spectrum of
protein–protein interactions and how the partners of interaction
modify the p53 structure and dynamics in wild-type and mutant
p53 to properly understand the regulatory mechanism of p53
stability due to the interactions with ubiquitinating enzymes and
chaperones. Indeed, the stabilization of mutant p53 is a prerequisite for its oncogenic GOF phenotype [1].
To make the scenario even more complicated, we have to
consider that although it is true that a large number of human
cancers feature p53 mutations or deletions, there is a large number
of other alterations that could indirectly impact on the p53 pathways. An example is provided by the amplification of its negative
regulators [13] that can modify p53 function and structure.
As an ideal master regulator of homeostasis, p53 features an
“antagonistic and paradoxical bifunctionality” a term coined in
studies of biological circuits and recently translated to p53
[4]. Indeed, as stated above, it exerts opposing effects on the cell,
including prosurvival activities that might sound contradictory with
its canonical pro-apoptotic functions, as well as it can have opposing effects on cell migration, metabolism, and differentiation
[4]. This is typical of a cancer gene with a dual role. P53 can indeed
regulate the expression of genes exerting diametrically opposite
Dynamics of p53
223
reshaping the network of p53 protein–protein interactions, and
introducing or silencing post-translational modification sites or a
combination of the mechanisms mentioned above. The emerging
mechanisms by which mutant p53 exhibits its GOF when it comes
to different protein-protein interactions are: (a) the formation of
complexes with other proteins that modify their activities (such as
p63 or p73); (b) the interaction with other transcription factors
(mainly VDR, SREBP, and Est2) that allows regulating promoters
that are generally not under wild-type p53 control; and (c) the
remodeling of chromatin through interactions with chromatinremodeling proteins (such as SWI-SNF CRC and Pontin) or inducing chromatin regulatory gene expression (for example MLL1,
MLL2, and MOZ). These mechanisms are not mutually exclusive
in the onset of different cancers and are also likely to be contextdependent [1].
Mutant p53 proteins have been for a long time expected to be
“undruggable” but recent studies suggest the opposite, as recapitulated in a comprehensive review article [12]. These studies provide important proofs of concept that it is possible to rescue the
structural mutants of p53. However, several efforts are still required
in the direction of cancer therapy and personalized medicine. In
this context, the identification of the complex mechanisms that
trigger mutant p53 GOF activities becomes essential to provide
tailored solutions for new treatments to undermine mutant p53
activities.
It is also essential to understand in detail the spectrum of
protein–protein interactions and how the partners of interaction
modify the p53 structure and dynamics in wild-type and mutant
p53 to properly understand the regulatory mechanism of p53
stability due to the interactions with ubiquitinating enzymes and
chaperones. Indeed, the stabilization of mutant p53 is a prerequisite for its oncogenic GOF phenotype [1].
To make the scenario even more complicated, we have to
consider that although it is true that a large number of human
cancers feature p53 mutations or deletions, there is a large number
of other alterations that could indirectly impact on the p53 pathways. An example is provided by the amplification of its negative
regulators [13] that can modify p53 function and structure.
As an ideal master regulator of homeostasis, p53 features an
“antagonistic and paradoxical bifunctionality” a term coined in
studies of biological circuits and recently translated to p53
[4]. Indeed, as stated above, it exerts opposing effects on the cell,
including prosurvival activities that might sound contradictory with
its canonical pro-apoptotic functions, as well as it can have opposing effects on cell migration, metabolism, and differentiation
[4]. This is typical of a cancer gene with a dual role. P53 can indeed
regulate the expression of genes exerting diametrically opposite
Dynamics of p53
223