2. contents
Introduction
History
Description of the gene
Structure of gene
Mechanism of working for p53
Role of p53 in treatment of various cancers
Potential therapeutic use and significance of
p53
Future trends in p53
Summary and conclusion
references
3. Introduction
Cancer
Cancer is a class of diseases in which a group of cells
display uncontrolled growth , invasion, and sometimes
metastasis .
p53 as a tumor suppressor protein
P53 is a protein ,that is the product of a tumor
suppressor gene; it regulates cell growth and
proliferation, and prevents unrestrained cell division
after chromosomal damage, as from ultraviolet or
ionizing radiation. The absence of p53 as a result of a
gene mutation increases the risk of developing various
cancers.
4. history
The history of the tumor suppressor
protein 53
p53 was identified in 1979 by Arnold Levine, David Lane
and William Old, working at Princeton University,
Dundee University (UK) and Sloan-Kettering Memorial
Hospital, respectively. It had been hypothesized to exist
before as the target of the SV40 virus, a strain that
induced development of tumors. Although it was initially
presumed to be an Oncogene, its character as a tumor
suppressor gene was revealed in 1989.In 1993, p53
protein has been voted molecule of the year by the
Science magazine.
5. Description of the gene
The name p53 is in reference to its apparent molecular mass
53 kilo dalton.p53 protein was first identified in 1979 as a
transformation-related protein and a cellular protein which
accumulates in the nuclei of cancer cells .In subsequent
studies, p53 became widely recognized as a tumor
suppressor, and the p53 gene became probably the most
common site for genetic alterations in human cancers .
Presently, p53 is known to play a key role in practically
all types of human cancers, and the mutation or loss of
the p53 gene can be identified in more than 50% of all
human cancer cases worldwide.
6. Structure of the gene
Human p53 is 393 amino acids long and has
seven domains.
• N-terminal transcription-activation domain (TAD), also known
as activation domain 1 (AD1) which activates transcription
factors.
• Activation domain 2 (AD2) important for apoptotic activity.
• Proline Central DNA-binding core domain (DBD) . Contains one
zinc atom and several arginine amino acids.
• Nuclear localization signaling domain.
• Homo-oligomerization domain (OD).
• C-terminal involved in down regulation of DNA binding of the
central domain.
• A tandem of nine-amino-acid transactivation domains
(9aaTAD) was identified in the AD1 and AD2 regions of
transcription factor p53.
7. figure 1
Figure 1 : The structure of the core domain of the p53
protein bound to DNA (dark blue).The six most
frequently mutated amino acids in human cancer are
show in yellow – All are residues important for p53
binding to DNA –Red ball: Zinc atom
8. Mechanism of working
for cancer p53
In normal cells, the p53 protein level is low. DNA damage and
other stress signals may trigger the increase of p53 proteins,
which have three major functions: growth arrest, DNA repair
and apoptosis (cell death). The growth arrest stops the
progression of cell cycle, preventing replication of damaged
DNA. During the growth arrest, p53 may activate the
transcription of proteins involved in DNA repair. Apoptosis is
the "last resort" to avoid proliferation of cells containing
abnormal DNA.
9. A brief about several
mechanisms of cancer p53
• It can activate DNA repair proteins when DNA
has sustained damage.
• It can induce growth arrest by holding the cell
cycle at the G1/S regulation point on DNA
damage recognition.
• It can initiate apoptosis, the programmed cell
death, if the DNA damage proves to be irreparable.
10. Figure 2
In a normal cell p53 is inactivated by its negative
regulator, mdm2. Upon DNA damage or other stress,
various pathways will lead to the dissociation of the p53
and mdm2complex.Once activated; p53 will either
induce a cell cycle arrest to allow repair and survival of
the cell or apoptosis to discard the damage cell. How
p53 makes this choice is currently unknown.
11. In unstressed cells, p53 levels are kept low through a continuous
degradation of p53. A protein called Mdm2 (murine double
minute 2 also called HDM2 in humans) binds to p53, preventing
its action and transports it from the nucleus to the cytosol. Also
Mdm2 acts as ubiquitin ligase and covalently attaches
ubiquitin to p53 and thus marks p53 for degradation
by the proteasome. However, ubiquitylation of p53 is
reversible. A ubiquitin specific protease, USP7 (or HAUSP),
can cleave ubiquitin off p53, thereby protecting it from
proteasome-dependent degradation. This is one means by
which p53 is stabilized in response to oncogenic insults.
Phosphorylation of the N-terminal end of p53 by the above-
mentioned protein kinases disrupts Mdm2-binding.
Mdm 2: its significance
in mechanism of action of p53
13. • Role of P53 and MDM2 in Treatment Response of
Human Germ Cell Tumors
• Adenovirus-based p53 gene therapy in ovarian cancer
•
• p53 alterations in recurrent squamous cell cancer of the
head and neck refractory to radiotherapy
• Clinical studies of p53 in treatment and benefit of
breast cancer patients
• Boehringer Ingelheim and Priaxon announce a
collaboration to research and develop novel treatments
for cancer
• Regulation of cancer stem cells by p53
• P53 Gene Therapy: A Potential Panacea to Cancer
Role of p53 in cancer treatment
15. • Role of p53 Gene in Metabolism Regulation in Patients
with Li-Fraumeni Syndrome
• The role of p53 in treatment responses of lung cancer
• The Association of p53 with Specific Cancers
Potential therapeutic use and
significance of cancer p53
• Trifluorothymidine Induces Cell Death Independently of
p53
• Clinical significance of p53 alterations in surgically
treated prostate cancers
16. • Novel Regulatory Mechanism Identified for Key Tumor
Suppressor p53:
• p53 at the cross roads of cancer and ageing
• p53 status may be predictive of outcome in breast
cancer
• p53 and stem cells: new developments and new
concerns.
• Inhibition of p53 Transcriptional Activity: A Potential
Target for Future development of Primary
Demyelination
• Gene Therapy for Pediatric Cancer: State of the Art
and Future Perspectives
Future trends of p53 in curing
various cancers
17. • p53 was originally viewed as an oncogene,but during the
past several decades it has come to be understood to be a
tumor suppressor gene.During this time , many p53 family
transcriptional targets have been identified as having the
capacity to modulate various cellular processes including
growth arrest , apoptosis , senescence , differentiation , and
DNA repair.
• As chemotherapy show disadvantage of regrowth of cell ,
metastasis after surgery treatment , chemoresistance to
tumor, gene therapy has been a revolutionary step towards
cancer treatment
• This small pocket size molecule has yet to see a lot of
changes means sky is not the limit and the end of land on
earth might also not be its end in coming future.This
molecule being crowned also as the molecule of the year in
1999 promises that it will combat cancer by all its powers of
apoptosis and cell death only on the condition if people on
earth stop smoking there golden lives with a small “FOUR
SQUARE” and let mutations happen in p53.So lets stop being
exposed to harmful rays and be away from smoking and
more near life.Rest work the intelligent p53 will do on its
own.
Summary
