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. (1) 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? (2) 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-CIP 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? (3) 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 contains 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? 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. (1) 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? (2) 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-CIP 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? (3) 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 contains 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? (1) 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? (2) 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-CIP 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? (3) 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 contains 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. p21 is a downstream target for activated p53 in response to various types of stress. It is not constituitvely expressed in cells. Therefore, in mutant p53 forms since it is unable to activate p21, there is no detectable p21 protein present despite no mutations in the DNA sequence.

2. As stated in the above answer, p21 activation requires activated p53 under normal conditions in response to DNA damage. Now in the above question the promoter of p21 is constitiutive promoter which means that unlike the above conditional expression, the transcription of p21 will be always on which would lead to translation of p21 protein throughout, which inhibits cyclinE and its associated cdk. This helps in further signaling to p53 for further downstream actions. However, even if p21 expresses, there is no further normal p53 to carry the functions which is why in such mice there is delay in the formation of tumors. However, because of the lack of master regulator i.e p53...it eventually leads to tumor formation.

3. This seems to be a tricky situation but remember that mutations in p53 can also lead to gain of mutations which could then still be despite a normal functional p53 copy present.

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