certain biological contexts, p53 supports cell survival, even if in this
case the beneficiaries are the cancer cells [4]. A similar dual role has
been emerging in cancer for many other genes and processes,
suggesting that we need a more sophisticated understanding of
what these genes do at different cancer stages and in different
contexts.
Indeed, p53 is known for its role in multiple cellular pathways,
such as response to DNA damage or various cellular stresses, cell
cycle arrest, senescence, autophagy, and cell death [1]. P53 is also
responsible for maintaining homeostasis by repairing or eliminating
cells with a damaged genome [4]. P53 has even more multifaceted
functions, and it is also crucial for cell survival by promoting
autophagy and metabolism in starvation [1]. P53 signaling pathways are overall cell type- and context-specific [2].
P53 is mostly known as a transcriptional activator of several
genes through the recognition and binding of specific DNA
sequences [2, 5]. In normal cells, p53 is detectable at very low
levels, whereas it is post-translationally modified and stabilized in
response to stimuli such as DNA damage, ribosomal or metabolic
stress, and other alterations [2, 6]. P53 can then activate the
transcription of multiple genes that determine the cell fate toward
a survival or a death response [1]. P53 not only can initiate autophagy as a prosurvival mechanism but it is also tightly regulated by
autophagy itself, which downregulate p53 functions to prevent cell
damage [7]. In general, p53 can be controlled at multiple levels.
For example, p53 is involved in an elegant feedback loop in which
the protein can signal its destruction via the activation of Mdm2
(murine double minute 2) to restore normal conditions [1]. Mdm2
is an E3 ubiquitin ligase, which ubiquitinates p53 and targets it for
proteasomal degradation [8].
In light of its manifold functions, P53 has often been referred
to as the guardian of the human genome. Indeed, it monitors and
orchestrates the activities or slow down certain processes to maintain a properly functioning environment (i.e., the cell) [1]. In this
sense, P53 signaling pathways are overall highly cell type- and
context-specific. It becomes thus crucial to understand how,
where, and when it is activated and regulated in fine details.
P53 is the gene more frequently mutated in human cancers
[9]. In contrast to many other tumor suppressors, the most common alterations of p53 in cancer are missense mutations that can
result in the loss of transcriptional activity or in gain-of-function
(GOF) that triggers aggressive phenotypes. Indeed, missense mutations account for approximately 75% of all p53 alteration in human
cancers [10]. The fact that most p53 alterations in tumors are
missense mutations suggests that cancer cells expressing mutant
p53 have an advantage over the deletion of p53 [11].
The GOF of mutant p53 could be, in principle, achieved in
various ways, i.e., promoting the expression of different target
222
Elena Papaleo
case the beneficiaries are the cancer cells [4]. A similar dual role has
been emerging in cancer for many other genes and processes,
suggesting that we need a more sophisticated understanding of
what these genes do at different cancer stages and in different
contexts.
Indeed, p53 is known for its role in multiple cellular pathways,
such as response to DNA damage or various cellular stresses, cell
cycle arrest, senescence, autophagy, and cell death [1]. P53 is also
responsible for maintaining homeostasis by repairing or eliminating
cells with a damaged genome [4]. P53 has even more multifaceted
functions, and it is also crucial for cell survival by promoting
autophagy and metabolism in starvation [1]. P53 signaling pathways are overall cell type- and context-specific [2].
P53 is mostly known as a transcriptional activator of several
genes through the recognition and binding of specific DNA
sequences [2, 5]. In normal cells, p53 is detectable at very low
levels, whereas it is post-translationally modified and stabilized in
response to stimuli such as DNA damage, ribosomal or metabolic
stress, and other alterations [2, 6]. P53 can then activate the
transcription of multiple genes that determine the cell fate toward
a survival or a death response [1]. P53 not only can initiate autophagy as a prosurvival mechanism but it is also tightly regulated by
autophagy itself, which downregulate p53 functions to prevent cell
damage [7]. In general, p53 can be controlled at multiple levels.
For example, p53 is involved in an elegant feedback loop in which
the protein can signal its destruction via the activation of Mdm2
(murine double minute 2) to restore normal conditions [1]. Mdm2
is an E3 ubiquitin ligase, which ubiquitinates p53 and targets it for
proteasomal degradation [8].
In light of its manifold functions, P53 has often been referred
to as the guardian of the human genome. Indeed, it monitors and
orchestrates the activities or slow down certain processes to maintain a properly functioning environment (i.e., the cell) [1]. In this
sense, P53 signaling pathways are overall highly cell type- and
context-specific. It becomes thus crucial to understand how,
where, and when it is activated and regulated in fine details.
P53 is the gene more frequently mutated in human cancers
[9]. In contrast to many other tumor suppressors, the most common alterations of p53 in cancer are missense mutations that can
result in the loss of transcriptional activity or in gain-of-function
(GOF) that triggers aggressive phenotypes. Indeed, missense mutations account for approximately 75% of all p53 alteration in human
cancers [10]. The fact that most p53 alterations in tumors are
missense mutations suggests that cancer cells expressing mutant
p53 have an advantage over the deletion of p53 [11].
The GOF of mutant p53 could be, in principle, achieved in
various ways, i.e., promoting the expression of different target
222
Elena Papaleo