P53

INTRODUCTION:
  • p53 has been described as “GUARDIAN ANGEL OF THE GENOME” because it performs following mechanism:
  • DNA Repair Cell growth arrest
  • Apoptosis (programmed cell death)
  • P53 is also known as cellular tumour antigen Ag, phosphoprotein P53 or tumour suppressor p53.
  1. p53 is Located on Chr. 17
  2. p53 Encodes 53k Da protein
  3. P53 protein is encoded by TP53.
  4. The tumor suppressor p53 is a phosphoprotein barely detectable in the nucleus of normal cells.
  5. In non stressed, healthy cells, p53 has a short half-life (20 minutes), because of its association with MDM2, a protein that targets it for destruction.
  6. When the cell is stressed, for example by an assault on its DNA, p53 undergoes post-transcriptional modifications that release it from MDM2 and increase its half-life.
  7. Unshackled from MDM2, p53 also becomes activated as a transcription factor.
  8. The complexity of the p53 response makes this an ideal system for application of newly emerging rapid throughput analysis techniques and informatics analysis.
STRUCTURE & FUNCTIONS:
  • P53 has seven domains :
  1. N-terminus transcription activation domain (TAD) also known as Activation domain -1 (AD-1) .
  2. N-terminus contains two complementary TAD with major one at residue 1- 42 and a minor one at residues 55 – 75, specifically involved in the regulation of several pro-apoptotic genes.
  3. Activation Domain-2 (AD-2) important for apoptotic activity lies at residue 44-63.
  4. Proline rich domain important for the apoptotic activity of P-53 (64-92 residues).
  5. Central DNA binding domain (DBD) contains one Zinc atom and several arginine amino-acid (102-292). This region is responsible for binding the P-53 co-repressor LMO3.
  6. Nuclear localization signalling domain (NLS) (316-325).
  7. Homo-oligomerisation domain (OD) .Tetramerisation is essential for the activity of P53 in-vivo.
  8. C-terminal involved in the downregulation of the DNA binding of the central domain (356-393).
  • Oncogenic function of mutant p53 protiens:
  1. Dominant negative 
  2. p53 Arrests cell cycle at GI phase
  3. Loss of wild type p53 function
  4. Gain of function by:
  • Activation of specific target genes:EGR1
  • Downregulation of specific target genes Mst1
  • Interfernece with the apoptotic network regulated by AIF
  • Interference with AIF3 regulated cell death
  • Interference with the TGFb growth control pathway
  • Interference with Nfkb induced apoptosis
P53 REGULATION: DNA damage: Chemical carcinogens UV,γ & X irradiation
                   ↓←PARP
                 P53 → P21
        ↓             ↓           ↓ 

 DNArepair Apoptosis cell cycle arrest
        ↓             ↓           ↓ 
 Maintenance of genomic integrity

  • In normal cells p53 is inactivated by negative regulator, mdm2 complex.
  • Once activated,p53 will induce a cell cycle arrest to allow either repair and survival of the cell or apoptosis to discard the damaged cell.
  • The mechanism is still unknown.
  • P53 activates due to stress and performs two events : 
  • In first event, half life of the p53 increased drastically leading to a quick accumulation of p53 in stressed cell.
  • In second step, conformational changes forces p53 to be activated as a transcription regulator in the cells.
Role In Disease:
  • If the TP53 gene is damaged, tumor suppression is severely reduced. People who inherit only one functional copy of the TP53 gene will most likely develop tumors in early
  • adulthood, a disorder known as Li-Fraumeni syndrome.
  • Certain pathogens can also affect the p53 protein that the TP53 gene expresses. One such example, human papillomavirus (HPV), encodes a protein, E6, which binds to the p53 protein and inactivates it. This, in synergy with the inactivation of another cell cycle regulator, pRb, by the HPV protein E7, allows for repeated cell division manifested in the clinical disease of warts.
  • In healthy humans, the p53 protein is continually produced and degraded in the cell. The degradation of the p53 protein is, as mentioned, associated with MDM2 binding. In a negative feedback loop, MDM2 is itself induced by the p53 protein. 
Exam Question
  • p53 Encodes 53k Da protein
  • p53 is Located on Chr. 17
  • p53 Arrests cell cycle at GI phase
  • Half-life of p53 protein in normal cells is 20 minutes
  • Policemen gene’ or ‘Guardian gene’ is the name given to P53
  • P53 is the most common oncogene mutation causing malignancy in humans

Don't Forget to Solve all the previous Year Question asked on P53