p53 Flashcards
(23 cards)
What are the key structural domains of p53?
Central DNA-binding domain, tetramerisation domain, N-terminal transactivation domain, C-terminal regulatory domain.
Why must p53 form a tetramer?
Tetramer formation is required for full DNA-binding and transcriptional activity.
What are the main functions of p53?
Tumour suppression via cell cycle arrest, DNA repair, and apoptosis in response to cellular stress.
What role does p53 play in gene regulation?
Acts as a transcription factor activating genes involved in DNA repair, cell cycle arrest (e.g., p21), and apoptosis (e.g., BAX, PUMA, NOXA).
How does the extent of DNA damage affect p53’s actions?
Low damage → temporary arrest; High damage → triggers apoptosis.
How are p53 levels controlled under normal conditions?
Constantly produced and degraded via Mdm2-mediated ubiquitination.
How does Mdm2 regulate p53?
Binds p53, adds ubiquitin, and targets it for proteasomal degradation.
What happens when p53 is activated?
Phosphorylation of p53 (e.g., by ATM/ATR) prevents Mdm2 binding → stabilisation and accumulation.
What is the role of p14^ARF in p53 regulation?
Sequesters Mdm2 in response to oncogenic stress, allowing p53 stabilisation.
Name cellular stresses that activate p53.
DNA damage, UV/ionising radiation, oncogene activation, hypoxia, ribosomal stress, cytoskeleton disruption.
What are the downstream effects of p53 activation?
Induction of genes for cell cycle arrest (e.g., p21), DNA repair, and apoptosis.
How does p53 induce apoptosis?
Activates pro-apoptotic genes like BAX, PUMA, and NOXA → mitochondrial cytochrome c release → apoptosome → caspase cascade.
What is the role of Bcl2 in p53-mediated apoptosis?
Anti-apoptotic; inhibits cytochrome c release. PUMA/NOXA inhibit Bcl2 to promote apoptosis.
Why is the BAX:Bcl2 ratio important?
High BAX:Bcl2 promotes apoptosis; potential therapeutic target.
How does p53 interact with the pRB pathway?
p53 induces p21 → inhibits CDK/cyclins → keeps pRB active → blocks G1-S transition.
How common are p53 mutations in cancer?
p53 is the most commonly mutated gene in human cancers (~50%).
What happens if p53 function is lost?
Cells bypass G1/S checkpoint and avoid apoptosis → genomic instability → tumour progression.
What is loss of heterozygosity (LOH) in p53?
Mutant p53 interferes with wild-type p53 tetramers; selection pressure leads to loss of the second allele.
How can cancer cells escape p53 control besides mutation?
Mdm2 overexpression, p14^ARF inactivation, HPV E6 protein (binds/degrades p53), nuclear exclusion.
What is the link between p53 loss and genomic instability?
Without p53, damaged DNA is not repaired or eliminated → increased mutation rate and malignancy.
How might p53 be used in cancer therapy?
Gene therapy (wt p53), Mdm2 inhibitors (e.g., Nutlins), reactivators of mutant p53 (e.g., PRIMA-1met), p53-based vaccines.
What is “super p53”?
Genetically enhanced p53 with a stronger response to DNA damage; shown to resist tumour formation in mice.
What is synthetic lethality in p53-targeted therapy?
Targeting vulnerabilities specific to p53-deficient cells (e.g., PARP inhibitors in BRCA-mutant cancers).
