Page 75 - GPD-2-3

Gene & Protein in Disease Hotspots in the FOXO4: p53 interaction

1. Introduction interaction. This disruption leads to the disorganization
of the FOXO4-PML-DNA-SCARS complex, releasing
Cell senescence refers to the phenomenon of cell p53 from this complex and making it available to trigger
cycle arrest that occurs in response to cellular stress. p53-mediated apoptosis. The synthetic peptide FOXO4-
This arrest is accompanied by halted cell growth, an DRI can thereby reduce senescence and features of frailty
upregulated expression of cytokines, and an enhanced in a fast-aged mice model (XpdTTD/TTD). In addition,
[1]
secretory capacity . This phenomenon is also known as experiments also show that FOXO4-DRI can restore the
the senescence-associated secretory phenotype (SASP), loss of renal function in both naturally and fast-aged mice.
which is driven by various families of factors, including
interleukins, chemokines, growth factors, proteases, and As a result, the inhibition of protein–protein interaction
[2]
their regulators . The effects of SASP are two sided. On (PPI) by FOXO4-DRI exhibits promising potential in the
[11]
the one hand, it can inhibit tumor growth and promote treatment of senescence-related diseases .
the restoration and regeneration of damaged tissues. However, when compared with small molecules,
Conversely, the presence of abnormal cytokines can peptides have certain disadvantages, including limited
accelerate the aging process, contribute to tumorigenesis, membrane-penetrating ability, poor in vivo stability, low
and facilitate tumor metastasis [3,4] . Therefore, cell metabolic stability, and reduced oral availability [13,14] . In
senescence represents an important risk factor for cancer, addition, the production cost and market price of peptide-
as the accumulation of mutations and inflammation caused based drugs tend to be higher than those of small molecules.
by senescence can induce oncogenesis [1,5] . These limitations have constrained the development and
p53 is a critical tumor suppressor that plays an utilization of peptide-based drugs. However, therapeutic
important role in tumorigenesis and development . The peptides feature unique biophysical properties compared
[6]
human p53 protein consists of 393 amino acids. It contains to small molecules. Their larger size makes it easier to
five domains: the N-terminal transactivation domain, a inhibit PPIs, and their higher specificity can help avoid
[14]
proline-rich domain, the DNA-binding domain (FOXO4- side effects stemming from off-target effects . Given
DBD), the tetramerization region, and a carboxy-terminal the demonstrated strong potential of FOXO4-DRI, the
regulatory domain . p53 becomes activated in response to development of a small molecule mimic targeting the
[7]
various intracellular and extracellular signals, exerting its FOXO4-DRI: p53 interaction could provide a preferable
regulatory influence on tumor development through DNA route to antagonizing the FOXO4:p53 interaction. The
damage repair, cell cycle arrest, apoptosis, senescence, design of such a small molecule would benefit from an
and cellular stress responses [8,9] . Functionally, when p53 is improved understanding of the DRI: p53 interaction.
inactive, it not only loses its cancer-suppressing function While the interaction between FOXO4-DRI and p53
but also contributes to the promotion of carcinogenesis . holds significant promise as a therapeutic target, there
[10]
Research has shown that FOXO4 is upregulated in is currently no direct evidence regarding the molecular
senescent cells but is only marginally expressed in most interaction and binding site on p53 for the DRI. Mandal
other tissues . FOXO4 plays a crucial role in maintaining et al. reported that the interaction between two domains,
[11]
survival in senescent cells by repressing p53-induced p53-TAD (transactivation domain) and FOXO4-FHD
apoptotic response . DNA-SCARS, or DNA segments (forkhead domain), plays a crucial role in the formation
[12]
with chromatin alterations reinforcing senescence, is of the FOXO4-p53 complex . Le et al. showed that
[15]
known to fuse with promyelocytic leukemia (PML) bodies. a designed peptide (with a K value of 0.66 nM) can
d
This interaction leads to the recruitment of p53, thereby disrupt the FOXO4-p53 interaction by preferentially
forming a complex with FOXO4 . FOXO4 consists of binding to FOXO4 . Kim et al. demonstrated that the
[13]
[16]
several functional domains that contribute to its biological binding between two pairs of protein domains, FOXO4-
activities, including the forkhead domain (FH), nuclear FHD: p53-TAD (with a K value of 2.19 μM) and FOXO4-
d
localization signal (NLS), nuclear export sequence (NES), CR3:p53-DBD (with a Kd value of 6.96 μM), mediates the
C-terminal transactivation domains (TRD), and conserved FOXO4-p53 interaction . In addition, the N-terminal
[17]
regions (CR). region of FOXO4, the CRD (C-terminal regulatory
Baar et al. reported the development of a synthetic domain) of p53, and the DBD (DNA-binding domain) of
D-retro-inverso (DRI) FOXO4-based peptide known both proteins are involved in stabilizing the FOXO4-p53
as FOXO4-DRI, which is composed of D-amino acids complex . Given that the DRI is a synthetic D-amino
[15]
arranged in a reversed sequence and corresponds to acid retro-inverse sequence of residues 93–119 of FOXO4,
[11]
residues 93–119 of the FOXO4-FHD. This peptide has it is highly likely to possess a distinct molecular shape and
the ability to bind to p53 and disrupt the FOXO4-p53 charge distribution from that of the L-amino acids of the

Volume 2 Issue 3 (2023) 2 https://doi.org/10.36922/gpd.1491