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?

Explanation / Answer

Answer (1). p21 CIP is a cyclin dependent kinase inhibitor (CKI) which is constitutively expressed and is capable of inhibiting all cyclin/ CDK complexes. p53 cell cycle arrest in response to DNA damage is primarily mediated by p21 which causes downstream cell cycle arrest. It has been found that p21 protein is present in the cells expressing normal wild type p53 but not in case of mutated p53.

So this gives us the answer that here the mice have the p53 mutation so, the p21 CIP proteins were not detectable even when there was no mutation in either copy of p21 CIP gene.

Answer (2). p53 is a potent transcription factor which is activated in response to different stresses like oncogenic stress and induces cell- cycle arrest, apoptosis or senescence to protect the individual from cancer. This shows that p53 is involved in number of pathways which can lead to cancer, and p21 CIP is one example of it. Restoration of p21 does not correct the other pathways which are affected by mutated p53 but it can slow the tumor growth. Like p53 induces its own degradation by MDM2 but in mated form this doesn’t occur and p53 accumulates in cell. Similarly there are number of different pathways associated with p53 which can lead to tumor formation and its growth.

Answer (3). p53 gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Gene mutations are associated with a variety of human cancers. Alternative splicing of p53 gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants. Other reason can be it is because of dominant mutation occurring in the same gene.

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