Suppose you are studying a mouse strain known to contain a mutation in the p53 t

Question

Suppose you are studying a mouse strain known to contain a mutation in the p53 tumor suppressor gene As would be expected, almost 100% of these mice develop malignant tumors at a relatively young age. Please use your knowledge of the p53 pathway to rationalize the following experimental observations about these mice. A. Tissues from these mice do not contain detectable p21-CIP protein. However, DNA sequencing reveals that there are absolutely no mutations in either copy of p21-CIP. Why is p21 not expressed? B. p21-CIP expression can be restored to the mutant mice by crossing them with a strain that expresses p21-CIP from a constitutive ("always on") promoter. The resulting mouse strain still has the mutation in p53, but DOES express p21-ClP at normal levels. These mice are found to develop malignant tumors at a lower rate than the original strain, however, the tumor rate is still much higher than wildtype. Why does the new strain still get tumors even after restoration of p21-CIP expression? C. The mutation in the p53 gene is investigated and found to cause a single amino acid change in the DNA-binding region of the protein. However, it is found that the mouse strain is heterozygous for this allele, i.e, the mouse contain one completely normal copy of the p53 gene. In molecular terms, how can one mutated copy of this particular anti-cancer gene cause such a large increase in tumors?

Explanation / Answer

1. p53 binds to DNA and is a transcriptional activator of p21-CIP. A mutated p53 tumor suppressor gene, prevents the transcriptional activation of p21-CIP. Therefore, tissues isolated from p53 mutant mice do not contain detectable p21-CIP.

2. p53 is called the guardian of the genome. Active p53 leads to transcriptional activation of a large number of genes including but not limited to p21, GADD45, IGF-BP3, and Fas/APO1 which lead to cell cycle arrest, DNA repair, or apoptosis. p21 regulates the G1 cell cycle checkpoint which was compromised in the previous mice strains with mutated p53. The mouse strain which expresses mutated p53 but constitutively expressed p21 could still develop malignant tumors as the other cell cycle checkpoints and the apoptosis pathways of tumor suppression are still compromised.

3. p53 functions as a tetramer, therefore the occurence of a single mutated p53 in a tetramer with wildtype p53 may hinder the activity of the protein. Since the transcriptional and translational efficacies of wildtype and mutant p53 are not significantly different, the probability of oligomerization with atleast one mutant p53 monomer is very high. A mutation in the DNA-binding domain of the protein will signficantly alter the affinity of the tetramer for DNA, thereby compromising its tumor-suppressor activity.

Related Questions

Navigate

• Browse (All)
• Browse S
• Subjects

---

---

Integrity-first tutoring: explanations and feedback only — we do not complete graded work. Learn more.