Filomena Ferrentino MAT:1060100693
“The Guardian of the genome”, p53 , could confer a
second chance against cancer.
Premise
P53 protein , defined “the guardian of the genome ”, is a key player in the DDR( DNA damage
response), cell autonomous mechanisms which prevent genomic instability by repairing DNA,
arresting cell cycle or inducing cell senescence or apoptosis. P53 plays mainly its role acting as
genes’ regulator protein and, effectively, the most common mutations observed in p53 in human
cancers concern its binding DNA domain. Recent researches on pharmacological activation of
p53, which results inactive in different type of cancer, open new possible ways against cancer.
Results
Studies done by researchers of the Microbiology, Tumor and Cell Biology department of
Karolinska Institute in Stockholm, have demonstrated that p53 turns on genes that alert natural
killer cells. This first molecular evidence has been obtained in the colorectal carcinoma cell line
HCT116: using one of p53-activator , RITA (Reactivation p53 and Induction of cell cycle Apoptosis,
a drug entity preventing interaction between the gene encoding p53 and its most powerful
inhibitor, MDM2 protein), these researchers showed p53 reactivation results in more ULBP2
expressions on the carcinoma cell line surface, as well as on primary melanoma cells which are
then more effectively killed by NK cells in vitro assays.
Discussion
It’s possible p53 could be involved in modeling the extrinsic cellular defense against cancer as well
as in intrinsic cellular mechanisms. P53 tumor suppressor functions as a direct transcriptional
activator of ULBP2, a NKG2D receptor ligand located on Natural Killer cells. ULBP2, placed on
cancer cells surface, interacts with its immunoreceptor NKG2D, by stimulating the cytotoxic
function exerted by NK cells against above-mentioned cells. The binding of p53 to its response
element (RE) within the first intron of ULBP2 gene is required for the activation of its expression,
and this suggests a p53 direct effect on the immune response stimulation against cancer.
Importantly, this direct effect of p53 is independent of apoptosis or the ATM/ATR pathway, which
other researches demonstrated to be involved in the NKG2D ligands upregulation. Overall
researchers revealed that some p53-activating compounds may be valuable in cancer therapy,
because a single drug target may engage multiple anticancer pathways simultaneously. In
melanoma, for example, precancerous cells are held in check by the cell intrinsic DDR which can
also alert the immune-system through an ATM/ART dependent and p53 independent pathway.
When cancer progresses, loss of p53 function may lead to genomic instability as well as immunoevasion. Pharmacological reactivation of p53 may promote cancer regression by simultaneously
restoring the DDR and by re-alerting NK cells.
Next figure showed how
the intrinsic cell response
acts on precancerous cells
and alerts immune system
using ATM/ATR
dependent pathway. With
progress of cancers, loss of
p53 function causes
genomic instability
together with immunoevasion for the loss of NK
ligands expression.
Thanks to p53
pharmacological
reactivation you can
obtain a cancer regression
by simultaneously
restoring the DDR and by
re-alerting NK cells.
Conclusions
There are other studies ongoing to determinate p53 role in the ligands upregulation in other cells
line. Independent co-discovery of novel mechanisms is the most straight forward way to validate
new concepts! It’s therefore a new target for the pharmacological intervention and it’s crucial to
study the impact of the different molecules on p53 partners and indentify them in order to
maximize the potential combinatorial effect of the cell autonomous mechanisms induced by p53
and the NK-cell response triggered by p53 activation.
References
Guardian of the genome turns on genes that alert natural killer cells.
Jean-Marc Doisne, Thomas Chin Che Tan and Francesco Colucci ; University of Cambridge Clinical
School; Cambridge UK; University of Cambridge;
Cambridge UK; http://dx.doi.org/10.4161/cc.10.22.18196
A novel facet of tumor suppression by p53: induction of tumor immunogenicity.
Hai Li, Tadepally Lakshmikanth,Ennio Carbone and Galina Selivanova1,
Department of Microbiology; Tumor and Cell Biology; Karolinska
Institute;
Stockholm, Sweden; Tumor Immunology Laboratory;Department of Experimental and Clinical
Medicine; University of Catanzaro Magna Graecia; Catanzaro, Italy
Tumor suppressors control ULBP2, an innate surface ligand of the lymphocyteimmune receptor
NKG2D
Anja Heinemann and Annette Paschen
Department of Dermatology; University Hospital Essen; Essen, Germany