The tumor suppressor protein p53 is a redox active transcription factor that

organizes and directs cellular responses in the face of a variety of stresses that
lead to genomic instability. One of the most important questions in the study of
p53 is how selective transactivation of certain p53 target genes is achieved.
Reactive oxygen species (ROS), generated by cells as products or byproducts,
can function either as signaling molecules or as cellular toxicants. Cellular
generation of ROS is central to redox signaling. Recent studies have revealed
that each cellular concentration and distribution of p53 has a distinct cellular
function, and that ROS act as both an up-stream signal that triggers p53
activation and as a downstream factor that mediates apoptosis. Here, we
examine the newly discovered role of p53 in regulating cellular ROS generation
and how ROS modulate selective transactivation of p53 target genes. The focus
is on interlinks between ROS and p53.

Aerobic organisms are continually subjected to reactive oxygen species (ROS),

derivatives of O2 that are generated as products or byproducts by a plethora of
enzymatic reactions in life processes. Superoxide radical (O 2-) is the primary
derivative of O2 and it gives rise to hydrogen peroxide (H 2O2), alkoxyl/peroxyl
radical (RO/ROO), and peroxynitrite (ONOOH/ONOO). Reactions between ROS
and redox active amino acid residues (e.g., cysteine) in transcription factors
(e.g., AP-1, NF-B, and HIF-1) and enzymes (e.g., protein tyrosine phosphatases)
can modulate the activities of these proteins [1, 2]. Nature has integrated such
redox reactions into a variety of signaling pathways to regulate life processes [3
6], where ROS are recruited as second messengers [6,7]. Cellular processes in
which ROS are involved range from proliferation to growth arrest or senescence
and cell death [4,5]. Cellular generation of ROS is central to redox signaling. Site
of generation, spatial distribution, pulse concentration and temporal duration are
important parameters of ROS in governing target-specific transduction of redox
signals [5, 7, 8], and thus are subject to strict cellular scrutiny. ROS-generating
enzymes are compartmentalized [7] and tightly controlled at both the genetic
and activity levels [9, 10]; moreover, concentrations of ROS are exquisitely
balanced by non-enzymatic antioxidants (e.g., -tocopherol and glutathione
[GSH]) and antioxidant enzymes (e.g., superoxide dismutase [SOD] and catalase)
[7]. Correspondingly, antioxidant systems are also specifically organized. For
example, cellular thiol/disulfide systems form three distinct redox circuitries
(GSH/GSSH, Trx1 [-SH2/-SS-], and cysteine/cystine) to mediate differential
responses to physical and toxicological redox stimuli [11, 12]. When the balance
between oxidants and antioxidants tips towards the oxidant side, or when a
disruption of redox signaling and control occurs, oxidative stress ensues [11],
causing damage to bio-molecules such as DNA, proteins and lipids through
oxidative modification and contributing to the pathogenesis of human diseases
[3] and cytotoxicity of chemotherapy [13].

Tumor suppressor protein p53 occupies a pivotal position in maintaining genomic

integrity [14]. In response to cellular stresses that lead to DNA damage, wildtype p53 orchestrates transcriptions of numerous genes and directs cells either

to cell cycle arrest, senescence, or apoptosis via differential activation of target

genes [15], preventing the propagation of damaged DNA [16]. One of the most
important questions in the study of p53 is how p53 determines a specific cellular
outcome (e. g., selecting cell cycle arrest between senescence and apoptosis) via
selectively regulating certain groups of target genes. Current knowledge shows
that various effectors, including proteins and even non-coding RNAs (e.g., myc
[17], hCAS/CSE1L [18], Hzf [19], and miR-34 [20]), can play a role in selective
transactivation of p53 target genes that leads to different cellular outcomes.

Though it is generally recognized that oxidative stress is associated with p53dependent cell cycle arrest, DNA repair, and apoptosis, a clear understanding of
the mechanisms of the interactions between ROS and p53 is still elusive.

Gen penekan tumor TP53 (dulu P53) adalah salah satu gen yang paling sering
mengalami mutasi pada kanker manusia. Gen ini memiliki banyak fungsi dan
tidak dapat di klasifikasikan dengan mudah ke dalam kelompok fungsional
tertentu yang serupa dengan gen lain. TP53 dapat menimbulkan efek anti
proliferasi, tetapi yang tidak kalah penting, gen ini juga mengendalikan
apoptosis. secara mendasar, TP53 dapat dipandang sebagai suatu monitor
sentral untuk stress, mengarahkan sel untuk memberikan tanggapan yang
sesuai, baik berupa penghentian siklus sel maupun apoptosis. Berbagai stress
dapat memicu jalur respons TP53, termasuk anoksia, ekspresi onkogen yang
tidak sesuai, dan kerusakan pada integritas DNA. Dengan mengendalikan
respons kerusakan DNA, TP53 berperan penting dalam mempertahankan
integritas genom.

TP53 normal di dalam sel yang tidak mengalami stress memiliki waktu paruh
yang pendek (20 menit). Waktu paruh yang pendek ini disebabkan oleh ikatan
dengan MDM2, suatu protein yang mencari TP53 untuk menghancurkannya.
TP53 mengalami modifikasi pascatranskripsi yang membebaskannya dari MDM2
dan meningkatkan waktu-paruhnya. Selama proses pembebasan dari MDM2,
TP53 juga menjadi aktif sebagai suatu faktor transkripsi. Sudah ditemukan
lusinan gen yang transkripsinya dipicu oleh TP53. Gen tersebut dapat
dikelompokkan menjadi dua kategori umum-gen yang menyebabkan
penghentian siklus sel dan gen yang menyebabkan apoptosis.
Penghentian siklus sel yang diperantarai oleh TP53 dapat dianggap sebagai
respons primordial terhadap kerusakan DNA. Hal ini terjadi pada akhir fase G1
dan disebabkan terutama oleh transkripsi CDK1 dependen-TP53 CDKN1A(p21).
Gen CDKN1A, seperti telah dijelaskan, menghambat kompleks siklin/CDK dan
mencegah fosforilasi RB yang penting agar sel dapat masuk ke fase G1.
Penghentian siklus sel ini disambut baik karena member napas bagi sel untuk

memperbaiki kerusakan DNA. TP53 juga membantu proses dengan menginduksi

protein tertentu, seperti GADD45( penghentian pertumbuhan dan kerusakan
DNA), yang membantu perbaikan DNA. Apabila kerusakan DNA berhasil
diperbaiki, TP53 meningkatkan ( upregulate ) transkripsi MDM2, yang kemudian
menkan (down regulate) TP53, sehingga hambatan terhadap siklus sel dapat
dihilangkan. Apabila selama jeda kerusakan DNA tidak dapat diperbaiki,

P53 berfungsi sebagai pertahanan utama melawan kanekr dan seringkali

diaktivasi oleh banyak sinyal stress. P53 berfungsi seagai pengaktivasi proses
transkripsi, perbaikan DNA, apoptosis, dan penghambat siklus sel pada G1 dan
G2.

Platinum complexes are clinically used as adjuvant therapy of cancers

aiming to induce tumor cell death. Depending on cell type and concentration,
cisplatin induces cytotoxicity, e.g., by interference with transcription and/or
DNA replication mechanisms. Additionally, cisplatin damages tumors via
induction of apoptosis, mediated by the activation of various signal
transduction pathways, including calcium signaling, death receptor signaling,
and the activation of mitochondrial pathways.
Salah satu obat kemoterapi yang sering digunakan dalam kanker kepala dan
leher adalah cisplatin. Cisplatin, sebuah obat berbasis platinum, sering
digunakan sebagai terapi ajuvan kanker yang bertujuan untuk menginduksi
kematian sel. Cisplatin bekerja dengan mempengaruhi transkripsi dan/atau
replikasi DNA. Selain itu, cisplatin juga bekerja melalui induksi apoptosis,
dimediasi oleh aktivasi berbagai jalur transduksi. Sayangnya, kemampuan
sitotoksis dan induksi apoptosis cisplatin ini tidak terbatas hanya pada sel
kanker, sehingga cisplatin juga menyebabkan timbulnya efek samping seperti
toksisitas saraf, tulang, maupun ginjal dan depresi sumsum tulang.

Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in

cancer cells, thus, cisplatin might also lead to diverse side-effects such as
neuro- and/or renal-toxicity or bone marrow-suppression.