TUMOR PROTEIN 53 (TP53)
TUMOR PROTEIN 53/TP53
- One among “Tumor suppressor gene”.
- A Phosphoprotein, barely detectable in nucleus of normal cells.
- Also referred to as “Molecular policeman”/“Guardian angel of genome”
- Due to its protective role in cell cycle.
- Hallmarks of cancer.
- In non-stressed, healthy cells has short half-life~20 mins
- Due to its association with MDM2.
- MDM2 – Negative regulator of p53 tumor suppressor gene.
- Located on chromosome 17
- Encodes d on gene TP53 coding 53k Da protein
- Has seven domains.
1. Acts as “Tumor suppressor gene”.
- Anti-cancer effects due to,
- Enhances DNA repair, thus preventing mutations.
- Activates quiescence (temporary cell cycle arrest).
- Induces senescence (permanent cell cycle arrest).
- Promotes apoptosis of genetically defective cells.
2. Effects of p53 on cell cycle:
- Arrests cell cycle in G1phase by inhibiting Cyclin-Dependent Kinase (CDK).
- Damaged DNA repairs during this time.
- Normally when DNA damage is repaired by GADD45, p53 destructs itself & relieves cell cycle block.
- If DNA is unrepaired, p53 along with activated BAX & BAK gene induces apoptosis.
- Also induces senescence through LINC RNA.
3. Effects of p53 on cell repair:
- On cell stress/injury,
DNA assaulted due to anoxia/inappropriate oncoprotein activity
DNA damage sensed by (ATM & ATR) protein kinases
Kinases phosphorylate p53 & liberate it from MDM2.
p53 accumulates & suppresses neoplastic transformation.
EFFECTS OF p53 MUTATION:
- No cell cycle arrest.
- No DNA repair.
- Limitless replication leads to cancer.
- Increases susceptibility to cancers
- Li-Fraumeni syndrome.
- HPV encodes protein E6 binding to p53 thus, inhibiting its action.
- 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