Which mechanism best explains why cells with a mutant p53 protein (dominant-negative mutation) are more oncogenic than cells that simply lose one p53 allele?
- A Mutant p53 undergoes ubiquitin-mediated degradation faster than wild-type, reducing total p53 levels
- B Mutant p53 protein binds and inactivates the wild-type p53 tetramer, abrogating all p53 function with a single allele mutation ✓
- C Mutant p53 activates MDM2 transcription, leading to accelerated proteasomal degradation of the remaining wild-type p53
- D Loss of one p53 allele alone is sufficient for complete inactivation because p53 acts as a monomer
Correct answer: B. Mutant p53 protein binds and inactivates the wild-type p53 tetramer, abrogating all p53 function with a single allele mutation
Explanation
p53 normally functions as a homotetramer; dominant-negative mutant p53 proteins can oligomerise with wild-type p53 subunits and disrupt the entire tetrameric complex, functionally inactivating all p53 activity even when one wild-type allele remains. This is more potent than simple haploinsufficiency. MDM2 is actually a transcriptional target of wild-type p53 that provides negative feedback.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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