effects on the same process and can thus be envisioned as characterized by a dynamic “sliding scale” of functions that go from canonical tumor suppressor to common oncogenic properties [4].
The molecular mechanisms underpinning these opposing
responses induced by p53 have been linked to the diversity of the
DNA response elements, to a different spectrum of protein conformational changes and/or different chromatin configuration [4]. In
this context, p53 could be described as a transcriptional “super
hub” that dictates cell homeostasis, and ultimately decides the cell
fate by governing other secondary hubs in a tightly orchestrated
manner [4].
A major challenge is to decipher the mechanisms behind its hub
role and how p53 selects which hubs to engage and how its preferences can be modulated. An intriguing hypothesis is that the
paradoxical effects exerted by p53 could be related to differences in
their protein conformation [4, 14].
1.1 Cytosolic
and Mitochondrial
Functions of p53
P53 is also known for its transcription-independent functions [15–
17] related, for example, to mitochondrial apoptosis
[16, 18]. Indeed, p53 mutants with defects in transcription are
still capable of inducing apoptosis [19]. p53 can translocate to the
mitochondrial outer membrane in response to DNA damage. Here,
p53 binds to Bak/Bax to promote Bak/Bax oligomerization
[20]. As a consequence, mitochondrial outer membrane permeabilization (MOMP) is promoted, along with cytochrome c release,
caspase activation, and consequent apoptosis [21]. P53 can physically interact with pro- and anti-apoptotic members of the Bcl-2
family, i.e., not only Bak but also Bcl-2 and Bcl-xL, for example.
Different mechanisms could retain p53 in the cytosol and
prevent its mitochondrial translocation to restrict apoptosis under
normal conditions. Bcl-2, Bcl-xL and, Mcl-1 are known to directly
sequester the cytosolic p53 [22]. Moreover, K63-linked ubiquitination is associated with protein trafficking, and the cytosolic pool
of p53 is ubiquitinated through the K63 linkage, but such modification was not detected for the mitochondrial p53. Screening a
panel of E3 ligases, TRAF6 emerged as critical to control p53
mitochondrial translocation. TRAF6 indeed triggers p53
K63-linked ubiquitination in the cytoplasm, and it can reduce the
interaction between p53 and Mcl-1/Bak preventing localization at
the mitochondria and mediating activation of Bak. This mechanism
is prevented in genotoxic stress condition, in which TRAF6 can also
move to the nucleus where mediates the ubiquitination of p53 and
promotes, in this case, its acetylation and gene expression induction
of genes for cell survival under stress conditions [23].
Recently, another mechanism of p53-mediated transcriptionindependent functions has been proposed [24] that cytoplasmatic
p53 can stimulate the accumulation of Ca2+ ions within the endoplasmic reticulum (ER) by physically interacting with the ATPase
224
Elena Papaleo
The molecular mechanisms underpinning these opposing
responses induced by p53 have been linked to the diversity of the
DNA response elements, to a different spectrum of protein conformational changes and/or different chromatin configuration [4]. In
this context, p53 could be described as a transcriptional “super
hub” that dictates cell homeostasis, and ultimately decides the cell
fate by governing other secondary hubs in a tightly orchestrated
manner [4].
A major challenge is to decipher the mechanisms behind its hub
role and how p53 selects which hubs to engage and how its preferences can be modulated. An intriguing hypothesis is that the
paradoxical effects exerted by p53 could be related to differences in
their protein conformation [4, 14].
1.1 Cytosolic
and Mitochondrial
Functions of p53
P53 is also known for its transcription-independent functions [15–
17] related, for example, to mitochondrial apoptosis
[16, 18]. Indeed, p53 mutants with defects in transcription are
still capable of inducing apoptosis [19]. p53 can translocate to the
mitochondrial outer membrane in response to DNA damage. Here,
p53 binds to Bak/Bax to promote Bak/Bax oligomerization
[20]. As a consequence, mitochondrial outer membrane permeabilization (MOMP) is promoted, along with cytochrome c release,
caspase activation, and consequent apoptosis [21]. P53 can physically interact with pro- and anti-apoptotic members of the Bcl-2
family, i.e., not only Bak but also Bcl-2 and Bcl-xL, for example.
Different mechanisms could retain p53 in the cytosol and
prevent its mitochondrial translocation to restrict apoptosis under
normal conditions. Bcl-2, Bcl-xL and, Mcl-1 are known to directly
sequester the cytosolic p53 [22]. Moreover, K63-linked ubiquitination is associated with protein trafficking, and the cytosolic pool
of p53 is ubiquitinated through the K63 linkage, but such modification was not detected for the mitochondrial p53. Screening a
panel of E3 ligases, TRAF6 emerged as critical to control p53
mitochondrial translocation. TRAF6 indeed triggers p53
K63-linked ubiquitination in the cytoplasm, and it can reduce the
interaction between p53 and Mcl-1/Bak preventing localization at
the mitochondria and mediating activation of Bak. This mechanism
is prevented in genotoxic stress condition, in which TRAF6 can also
move to the nucleus where mediates the ubiquitination of p53 and
promotes, in this case, its acetylation and gene expression induction
of genes for cell survival under stress conditions [23].
Recently, another mechanism of p53-mediated transcriptionindependent functions has been proposed [24] that cytoplasmatic
p53 can stimulate the accumulation of Ca2+ ions within the endoplasmic reticulum (ER) by physically interacting with the ATPase
224
Elena Papaleo