molecular biology

1. p53 and Cancer
By
ASHISH KUMAR SHUKLA
M.S (Pharm) BIOTECHNOLOGY
BT/295

2. Cancer results from a series of molecular events that fundamentally alter the normal
properties of cells. In cancer cells the normal control systems that prevent cell overgrowth
and the invasion of other tissues are disabled.
These altered cells divide and grow in the presence of signals that normally inhibit cell
growth; therefore, they no longer require special signals to induce cell growth and division.
As these cells grow they develop new characteristics, including changes in cell structure,
decreased cell adhesion, and production of new enzymes.
What Is Cancer?

3. INTRODUCTION
•Tumor Suppressor
•53 kDa protein
•Encoded by TP53 gene
•Regulates cell cycle

4. HISTORY
The gene p53 was first discovered in 1979. A protein was identified in simian virus 40-
transformed mouse cells (SV40) by immunoprecipitation with anti-T serum. This protein was
called protein p53.
It was thought that the reason why scientists called the protein p53 is that the molecular mass of
this protein is 53kDa that is based on its migration in SDS gel.
Later the molecular mass was proved to be wrong, and the correct molecular mass should be
43.7kDa because p53 contains a proline-rich region, and this region can reduce the migration of
p53 in SDS gel. But the name ‘p53’ remained.
During the 1980s, the protein p53 was believed to be involved in the cell cycle, as well as
playing a role in DNA replication.

5. STRUCTURE

6. AMINO TERMINAL DOMAIN
• Transactivation
• Transcription factors – MDM2
PROLINE-RICH REGION
• Stability
CENTRAL CORE
• DNA binding domain
C-TERMINAL DOMAIN
• Negative regulation

7. •It can activate DNA repair proteins
when DNA has sustained damage.
Thus, it may be an important factor
in aging.
•It can arrest growth by holding
the cell cycle at the G1/S regulation
point on DNA damage recognition (if it
holds the cell here for long enough,
the DNA repair proteins will have time
to fix the damage and the cell will be
allowed to continue the cell cycle).
•It can initiate apoptosis (i.e.,
programmed cell death) if DNA
damage proves to be irreparable.

8. Chemical Carcinogens
• Direct acting vs. indirect
• Indirect results from non-reactive chemicals being
metabolized in liver to carcinogen
• Oxidative reactions by p450 enzyme complexes rid
body of fat soluble toxins
• Active carcinogen binds to DNA and causes mutations
(e.g., benzopyrene in cigarette smoke causes G to T
transversions in DNA – causes mutations of p53 at codons
175, 248 and 273)

9. Initiators vs. Promoters
• Initiators
• Carcinogens that interact with and cause mutations in DNA
• Promoters
• Interact with cells to promote growth, block differentiation
• Leads to additional permanent changes after initiator damage
• Does not cause cancer by itself
• No reliable test yet found to identify promoters

10. Radiation Mutations
• Ultraviolet radiation
• Ionizing radiation
• Gamma- and X-rays
• Particle radiation (alpha, beta)
• Electromagnetic radiation
• Power lines, cell phones, etc.
• May act as promoter

11. Cancer Treatments
• Surgery
• Chemotherapy
• Radiation therapy
• Photodynamic therapy
• “Magic bullets”
• Angiogenesis inhibitors
• Transplantation of hematopoietic stem cells
• Whole body radiation to treat metastases
• Gene therapy
• Reintroduce p53 or other tumor suppressor genes
• Must get into each and every cancer cell